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Translational Chemical Gap assessment for advancing discovery, development and precision

As yesterday’s lead enters today’s clinical trial, the standard operating script seems to call for product developers and clinicians to push away the originating basic , lest their lofty impractical ideals disrupt a delicate balance of strategic compromise. Indeed many scientists may not understand the competing push and pull of versus and quality versus production costs. They do, however, know the molecule in question intimately. Their insight into subtle vagaries of the incumbent can prove invaluable in clearing unexpected hurdles. The sophisticated techniques they applied to advance the molecule this far have not lost their analytical magic. They may very well save your bacon!

By Dr Mukund ranslational research should never be con- tional chemical biology effort is guided by several Chorghade, sidered a relay race hand-off, but rather a key factors: the impact of precision medicine, the Dr Michael Liebman, Tmarch together, hand-in-hand, toward a reality of the ‘valley of death’ and what natural Dr Gerald shared victory. In order to foster pragmatic collab- compounds and their clinical use can teach us. Lushington, oration, we endeavour to examine key technologies These issues are critical to improving drug develop- Dr Stephen Naylor that not only enable early stage discoveries, but can ment and lowering barriers to their translation into and Dr Rathnam also bridge the late-stage pitfalls that may threaten clinical utility and commercial value. Target-based Chaguturu promising drug candidates on the path to market. , a solely bottom up rather than top Translational chemica l biology sits at the nexus down approach, limits effective translation, partic- of and biology. While the application of ularly when viewed as the progression from labo- chemical biology principles helps in the designing ratory to . Observational therapeutics, guided of a bona fide chemical probe, it is translational by the principles of reverse – the chemical biology that helps translate basic research bedrock of but lately forgot- into meaningful clinical applications. This trajecto- ten by the – holds the key ry of chemical biology to its applied domain is to the bench to bedside holistic seesaw pendulum. interdisciplinary, and one that is yet to be mastered by academia. Succes sful outcome of any transla- Current drug approvals While biotechnological advances, and high throughput screenings or combinatorial and asymmetric syntheses have long promised new vis- Remember the old advice that you should “dance tas in drug discovery, the pharmaceutical industry with the one who brought you”? Translational is facing a serious innovation deficit. The costs of have escalated, the number of researchers would do well to heed this adage drug withdrawals has increased to historic highs and the transition from bench to bedside has been

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long and arduous. It is instructive to evaluate the ‘valley of death’ conundrum from the perspective of the drug approval process and drug product output. In 2016, the US FDA approved 22 New Molecular Entity (NME) and New Biologic License Applications (BLA) from a total of 41 actu- al filings. This was the worst year since 2010, when only 21 NME and BLA were approved from 23 filings. This is capture d and summarised for the past 10 years in Figure 1, which shows the total number of NME/BLA filings and approvals as a of each calendar year1. New drugs approved in 2016 included eight fast track designations (drugs that address unmet med- ical need); seven were deemed breakthrough treat- ments (clinical evidence indicated substantial improvement over other therapies); 15 received a priority review (six months instead of the standard 10 months); and six were accorded accelerated approval (for drugs that demonstrated superior ing to review the past 70 years of new drug activity Figure 1 performance over existing therapies for life-threat- at the FDA2. There has been a slow but notable New Molecular Entity (NME) ening disease indications). The FDA has intro- trend in the increased number of new drugs intro- and New Biologic License Application (BLA) filings and duced these designations over the recent past in duced into the US market by the FDA on a per approvals per calendar year. order to expedite the drug discovery and develop- decade basis. For example in the 1940s (1940-49) Taken directly from Reference ment process and hasten superior drug perfor- 192 new drugs were introduced, subsequently 1. * This information is mance candidates to market in or der to meet 1950s-200; 1960s-151; 1970s-170; 1980s-217; accurate as of December 31, urgent, unmet medical need. 1990s-311; 2000s-235 and projected for 2010- 2016. In rare instances, it may be necessary for the FDA to Janet Woodcock, Director of the Center for 2019-3212. Based on these approved drug num- change a drug’s NME Drug Evaluation and Research at the FDA, noted bers and , proponents of the pharmaceutical designation or the status of its that “..a lower than average number of novel sector argue that the Drug Discovery and application as a novel BLA drugs” were approved in 2016 by the FDA1. Development process is functional and innovation However, she claimed that the quality, impact and and creativity is alive and well. There is also an unique contributions to improved patient medical argument made that the ‘valley of death’ is over- care was extremely high for these approved NME hyped and overemphasised. and BLA therapeutics. For example, eight of th2e 2 approved drugs were first-in-class, representing Translational chemical biology – new drug-target mechanisms of action. In addition, the knowledge deficit nine approved drugs received rare or orphan dis- Since the launching of the National Institutes of ease status. This designation applies to disease (NIH) Roadmap Initiative, NIH continues indications that afflict less than 200,000 individual to invest millions of dollars to harness the reper- patients, and is significant because often times such toire of druggable therapeutic targets that have patients have no available therapeutic options. come to life from the human genome-sequencing Woodcock argued that “more important than the project. This effort made the academic quantity of novel drugs approved in 2016 is their appreciate, if nothing else, the ingenuity of its medical value and the important new roles they are brethren from the pharmaceutical industry in the serving to advance patient care.”1 discovery and development of drugs. NIH’s invest- The ‘quality versus quantity’ argument has some ment resulted in the development of exciting validity given recent trends in marketing new drugs technologies, brought high throughput screening that possess modest, incremental performance to the academic corridors, thousands of com- capabilities compared to other same in-class drugs pounds screened, millions of data points generated, (eg ). However given the vast number of dis- data analytics became the mainstream language, ease indications with minima l, or ineffective, treat- made inroads in optimising screen hits and ment options, it is imperative to increase the quan- strengthened chemical biology as a discipline in tity as well as the quality and effectiveness of new designing chemical probes. While this list of drugs coming to market. In that regard it is reveal- accomplishments comes across as seemingly

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impressive, the chemical probes discovered translational chemical approach. through this effort (almost) never saw the of Modern day the day, especially from a clinical perspective. (CombiChem)/high throughput synthesis and Inability to secure intellectual property rights and screening were amenable only to production of the dearth of expertise proved libraries of flat, planar with remarkable too steep a hill for the academic scientist to climb. lack of chirality and scaffold diversity. Creative Lack of translational medicine experience con- biology has been retrofitted to mundane, unin- tributed to a non-starter in what makes a therapeu- spired and uninspiring chemistry. Moreover, plant- tic tar get hit leap from being an active derived molecules with embedded chirality, or syn- compound to become a candidate with clinical thesised with high stereospecificity have been potential. This is translational chemical biology, neglected over many years due to proclaimed diffi- and is still in its infancy in both academia as well culty in securing intellectual property and per- as in many budding companies. ceived problems in obtaining large quantities of NIH has made a strategic effort in addressing this materials. Critics suggest: “We have become high knowledge deficit by instituting Small Business throughput in technology, yet have remained low Innovation Research (https://sbir.nih.gov/) grants throughput in thinking.” Post-marketing failures program to bring pharma ceutical experience to of blockbuster drugs have become major concerns entrepreneurs, and support research and develop- of industry, leading to a significant shift in favour ment that has a strong potential for commercialisa- of single to multi-targeted drugs and affording tion. Even with research dollars available, it is greater respect to traditional knowledge. The typi- incumbent upon the chemical to learn cal reductionist approach of modern science is and implement the principles of translational being revisited over the background of systems medicine as discussed in the ensuing sections. biology and holistic approaches of traditional practices. Translational chemical biology for drug Deploy modern tools to augment discovery is useful; it is extremely imperative that scientists’ repertoire the newer tools and techniques are brought to the The mismatch between academic efforts and that forefront. Sophisticated organic synthesis must still of industry is clearly of some concern. The phar- be the order of the day. maceutical sector may argue that the drug discov- Professor Robert Burns famously stated: “The ery and development process is already efficiently art and science of chemistry is one that is more eas- aligned. We would suggest that the efforts of the ily exemplified and epitomised than it is articulated academic may need to be somewhat and summarised.”3 We discuss herein, some realigned if they are to participate in contributing approaches and technologies that can indeed pay Figure 2 and improving the drug discovery and develop- rich dividends in discovering and progressing a R&D paths for natural ment process. In part this can be done by a more bioactive from mind to marketplace. products careful consideration of implementing a useful - observational therapeutics Reverse pharmacology is the development of drug candidates by validation of clinically-docu- mented experiential data on plant-derived natu- ral products4,5. In this approach, scientists and clinicians inte- grate bedside-documented experiential clinical data from plants used in Indian Traditional Medicine (Ayurveda) and from Chinese Traditional Medicine. Reverse pharmacology involves isola- tion, structure elucidation and biological mecha- nism of action studies on active compounds and assessment of novelty. One can expand on the already known activities of natural products derived from reverse pharmacology by selective functionalisation, generation and derivatisation of privileged structu res and conducting selective stud- ies on pre-clinical development. As the starting

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Figure 3 Fast-track path of reverse pharmacology

point(s) are compounds with established safety and follows a reverse pharmacology path from efficacy, one can then establish early proof of con- to laboratories (Figure 3). cept in humans and differentiation. Scientifically-validated and technologically-stan- Renaissance of plant-based dardised botanical products may be explored on a natural products fast track using innovative approaches such as Natural products have been historically regarded reverse pharmacology and systems biology, which as rich sources of novel molecules of broad utility are based on traditional medicine knowledge and architectural complexity4,5. The natural world (Figure 2). is a source for inspiration for and biolo- Many modern drugs have their origin in gists. The exquisite and varied architecture of nat- ethnopharmacology and traditional medicine. ural products provides a rich palette for discovery. Indian Ayurvedic and traditional Chinese systems Natural products can be considered ‘pre-validated are living ‘great traditions’. Ayurvedic knowledge by ’, having been optimised for interaction and experiential databases can provide new func- with biological through - tional leads to reduce time, money and toxicity – ary selection processes. Embedded in these bioac- the three main hurdles in the drug development. tive natural products are a number of diverse, chi- Extensive information on Ayurvedic medicine ral functional groups that are potential sites for research, clinical experiences, observations or binding. This diverse source of novel, avai lable data on actual use in patients can be used active agents serves as leads/scaffolds for elabora- as a starting point. Principles of systems biology tion into desperately-needed efficacious drugs for a where holistic yet rational analysis is done to multitude of disease indications. address multiple therapeutic requirements are coa- The chemical entities present in lesced with chemistry. Since safety of the materials may or may not be useful as a drug, just like the is already established from traditional use track hits from a target-based high throughput screen. records, it is necessary to undertake pharmaceuti- However, their activity can be enhanced either by cal development, safety validation and pharmaco- making modifi cations or combining with other dynamic studies in parallel to controlled clinical similar pharmacological activities that will make studies. Thus, drug discovery based on Ayurveda these hybrid molecules more drug-like. Scientists

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must aim to reconfigure products into chemical source of remarkable levels of diversity in natural hybrid ‘molecular legos’ and to screen the deck of products and investigational agents. diverse compounds against targets. Investigations The enthusiasm for natural products discovery should centre on: has sometimes been dampened by difficult synthe- i) Expansion of the already-known activities of ses. A significant disadvantage of natural products, natural products derived from reverse pharmacol- with the exception of those derived from fermenta- ogy by selective functionalisation, generation and tion, is the draconian organic synthesis/medicinal derivatisation of privileged structures and conduct- chemistry effort required for commercialisation or ing selective studies on pre-clinical development. future functionalisation. In many cases, the natural- ii) Designed organic synthesis of high recognition product compound has not been available in suffi- libraries focused on specific biological targets. cient quantities for various biological assays, there- iii) Synthesis of building blocks/scaffolds/high by limiting their exploration. Plant-based natural value intermediates. products are at times available in greater quantity.

5 Hybrid molecules 5 5 2 Recently, the concept of hybrid molecules has gained currency. Couplings of diverse molecules 5 * XDQLGLQH FDUERQDWH 2 + such as artemisinin and chloroquine with

1 &O +2 5 . 2 + 1 K3 have generated new molecules with effective- 5 ness in oncology. The therapeutic properties of sev- 1 1+ eral natural and synthetic products can be modu- 1 &O lated by such hybrids, possible to get alternate therapeutic indications, and hybrids can be struc- tural or functional. Expanding Hybrid molecules can also be made with differ- The ability to easily access new chemical space, ent molecular scaffolds in the same structure: however defined, is a major challenge for discovery Synthesis of differently substituted 2-[2-amino-6- chemists. Although advances in diversity-oriented (2-chloroquinolin-3-yl)-5, 6-dihydropyrimidin-4- synthesis have made great strides towards expand- yl] phenol (see diagram). ing the accessibility of synthetic compounds that Future investigations can centre on i) expansion have high levels of diversity (including stereochemi- of the already-known activities of natural products cal, shape and bond connectivity), there is room for derived from reverse pharmacology by selective further improvement. The diversity expansion inher- functionalisation, generation and derivatisation of ent in transformations that mimic the of privileged structures and conducting selective stud- small molecules and natural products can, in con- ies on pre-clinical development; ii) designed - junction with modern synthetic , ic synthesis of high recognition libraries focused on provide a new direction in the pursuit of natural specific biological targets; and iii) synthesis of product-derived substances. Simple and well-con- building blocks/scaffolds/high v alue intermediates. trolled transformations (oxidation, halogenation and alkylation) can afford compounds that have Flow chemistry unique structures that possess a wide range of In recent years flow chemistry has become a pow- physicochemical and biological properties (Figure erful tool for the rapid optimisation and refine- 4). Indeed, such biomimetic transformations are the ment of organic reactions and processes6,7. Most

Figure 4 Pursuit of natural product- derived substances

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are typically employed on a micro scale for proof tional exploitation of data on-hand may provide a of principle studies, modifications allow flow to be critical helping hand for navigating the ‘valley of also used for bulk production of candidate com- death’. pounds of interest. The three most common vari- To understand the strengths of computational ants of flow chemistry are micro flow, meso flow chemistry at various stages in the drug develop- and tethered reagent flow. Flow offers many ment process, let us consider how such tools are advantages over conventional batch chemistry: used. Early in the basic science stage of a chemical pressurisation allows reactions to be performed at biology investigation, modelling and informatics temperatures exceed ing the boiling points of sol- methods may (with a level of confidence similar to vents, multi-step reactions can be performed in a primary screening assay) provide glimpses of fac- continuous sequence and gaseous reagents can be tors that could play roles in a given physiological incorporated into reaction sequences with limited process and the modulation thereof. Such early effort. The processes are also amenable to rapid phase investigations, however, tend to be idea-rich automation, improving throughput in the discov- yet data-poor. Without a solid basis of reliable ana- ery phase. Additionally, improved impurity pro- lytical measurements or empiri cal understanding, files, one of the benefits of the controlled mixing/ such speculative glimpses bear little predictive heat transfer characteristics tha t the method offers, value. The veracity of computer-generated obser- is typically observed, as in the case of microwave vations may be difficult to assess in such an envi- mediated synthesis. The flow approach allows ronment, or if the analysis elucidates real phenom- rapid assembly of diverse libraries of building ena, it may not be immediately clear that these fea- blocks for synthesis, one can envision its use in tures have a strong bearing on the key issues of optimising a number of intra and intermolecular medical interest. transformations, including bioconjugations, PEG- By contrast, in the later, translational stages of ylations and glycosylation of NP building blocks. an investigation, one is almost always better armed with extensive data and empirical experience. Bound reagents: The use of bound reagents and Much of this insight can be directly leveraged to scavengers is an emerging technology frequently intelligently select computational protocols that employed in streamlining reaction set-up, work-up can be shown to reproduce what is already known, and purification. A key advantage of the use of and to foster effective method and parameter cali- bound reagents is the ease of conversion of batch bration that optimise the methodological fidelity reactions into flow format. This has been demon- for de novo calculations. strated by Ley et al on a number of examples, such As a practical example, the early stage applica- as the synthesis of oxomaritidine6. There is a huge tion of molecular modelling and chemical infor- variety of commercially-available and made-for- matics analyses (eg, docking and QSAR respective- purpose resi ns that can be employed. These include ly) toward hit elaboration will typically be con- oxidants, reductants, bases, acids and bound or stricted by either the small size, or the great hetero- encapsulated catalysts. geneity, of bioactivity data. Later on, after many laboratory studies have compiled homogeneous Chemoinformatics data sets spanning a good number (one can expect It is tempting to regard molecular modelling and at least several dozen) of close structural analogs to chemical informatics as predominantly ‘basic sci- the , this basis of knowledge ence’ tools – abstract engines for hypothesis gener- enables far more rigorous computational percep- ation, rather than rigorous techniques for address- tion of subtle SAR trends. This perception can fos- ing the advanced, fine tuning requirements of ter accurate refinements in deliverability, efficacy, translational drug optimisation, wherein promis- target specificity, toxicity, or a host of other impor- ing leads are tweaked for efficacy, selectivity, toxi- tant concerns. city and deliverability. In truth, however, this pre- When the existing data contains biomolecular conceived notion of computational analysis has lit- structural insight (eg, crystal structures or tle pragmatic or logical basis. When both the NMR), one can employ data trends to train methodological strengths of computational chem- detailed Comparative Binding (COMBINE) istry and the specific requirements of translational models that prioritise specific -receptor inter- science are considered, it is actually easier to argue actions according to favourable or problematic that modelling and informat ics have significantly contributions to the observed SAR (Figure 5)8. If greater aptitude for the later stages of therapeutic the data do not contain receptor structure informa- optimisation process. Indeed, rigorous computa- tion, computational methods can still prove very

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Figure 5 Receptor spatial features elucidated by comparative binding energy (COMBINE) training over bound ligand- receptor interactions and observed affinities. COMBINE training identifies receptor binding features that afford favourable and unfavourable sterics, H-donor and H- acceptor interactions. The receptor shown is the Lck and ligands are Gleevec derivatives

helpful. Machine learning methods are exception- synthetic impurities, or that may emerge (post- ally well suited for parsing the properties of specif- administration) due to metabolic conversions. ic hits or lead-analogs and contrasting those fea- Since trace impurities and may num- tures against therapeutic efficacy, selectivity or tox- ber in the dozens or hundreds of distinguishable icity assessments9. Such analyses can pinpoint the chemical entities, few regulatory boards require precise combination of desirable molecular that they all be subject to exhaustive attributes that favour some candidate ligands over testing. However, some quantifiable risk assess- others, and can suggest opportunities for further ment is nonetheless required, and a commonly re finement, as well as plausible tradeoffs, such as sought level of diligence entails computational those between efficacy and drug deliverability, or assessment of any toxic or mutagenic indications, between pathogen cytotoxicity versus host toxicity. or other potential adverse consequences. An impressive array of lead optimisation issues Requested evaluations rarely require unanimous may be plausibly addressed through protocols that declaration of non-toxicity across a broad range of rely at least in part on molecular modelling or chem- predictive measures. Instead, approval is generally ical informatics. Such issues include (among other granted if the petitioner can provide assurances things) many aspects of oral availability10, volume from at least two unrelated computational tech- of distribution11, brain barrier permeabili- niques that the threshold of for any ty12, pharmacodynamics13 and pharmacokinet- given trace entity is below the quantity presented in ics14. Computational techniques are also relied a standard dose, or in the metabolic process there- upon for the design of non- formula- of. A significant number of free internet-accessible tion components suitable for stabilising a therapeu- computational resources are available for such tic15 or facilitating its integration into pill form16. determinations, including packages based on either Great reliance may also be placed on modellers QSAR model training17 or on empirical toxic and informaticians in Phase II and Phase III clinical effect rules18. filings for the assessment of trace component toxi- One final area where chemical informatics is city. Specifically, while there is no substitute for blending with sophisticated new careful and incontrovertible in vivo toxicology methods toward enhancing translational aspects of testing of the primary therapeutic ingredient or any pharmaceutical practice is in precision medicine, drug formulation, late stage scrutiny of medicinal whereby new software tools19 are emerging to formulations places significant emphasis on exploit personalised genome profiling, in combina- prospective complications that may arise from tion with extensive chemical biological data in order trace contaminants present in the formulation as to predict toxicity and efficacy on a patient level.

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Process chemistry/route selection genase . All heme that are activat- Knowledge of process chemistry is pivotal to ed by hydrogen peroxide, including catalases, per- activities in the path of a drug from concept to oxidases and ligninases, function via a two-elec- commercialisation. Medicinal chemistry synthesis tron oxidation of the ferric resting state to an oxo- routes are low yielding and fraught with capri- ferryl porphyrin cation radical. cious reactions, tedious and While this oxidation state has yet to be charac- scale-up problems. Research by the authors and terised for the cytochro mes P-450, most of their their collaborators/teams led to development of reactions and those of the biomimetic analogues novel, cost-efficacious, scalable processes for chi- can be accounted for by oxygen transfer from/to a ral molecules natural and synthetic. Processes variety of substrates to give characteristic reactions were efficient: development of new methodologies such as hydroxylation, epoxidation and het- resulted in more than 100-fold reduction in costs eroatom oxidation. Other products resulting from and dramatic increases in reaction efficiencies and hydroxyl and hydroperoxyl radicals have also been yield. Prominent among these drugs were detected. The metabolic processes in vivo con- (Gabitril), Ziprasidone, Celiprolol CMI tribute in substantial measure to the eff icacy, side- 977 and CMI-392. These concepts for ‘Process effects and also the toxicity of a pharmaceutical Chemistry-Driven Drug Discovery’ have been entity. These factors are responsible for the success back-integrated into drug discovery methodolo- or failure of a clinical candidate. Metabolic pro- gies and have led to the discovery of new chemical cesses of drugs are always the subject of intense entities for clinical development. A unique combi- scrutiny in pharmaceutical companies. Pharma- nation of creativity with sophisticated technology, cologists have traditionally been involved with iso- strategic collaboration, global commerce and lation and identification of the metabolites of a refined logistics led to discovery of new drugs. The drug. It is imperative to conduct such studies early essential complement of expertise in chemistry in the drug development process. Toxicological and infrastructure facilities allied with strong and pharmacological studies on the metabolites institutional linkages built up with various univer- form a crucial segment in the identification of a sities and pharmaceutical industry ensured suc- clinical candidate20-26. cessful upscaling, seamless technology transfer Several problems are currently associated with and implementation of new technologies. the use of biological systems in studying : Drug metabolism: the case i) In vitro studies produce very small quantities of of cytochrome P-450 the product. Primary metabolites are often , involving co-administration of sev- hydrophilic and difficult to isolate. Most of the eral drugs, is common among the elderly and reactive metabolites and unstable intermediates are chronically ill. It is a risk factor for adverse drug reacted away by the biological nucleophiles. reactions and drug-drug interactions (DDI). One ii) Animal studies necessitate the sacrifice of ani- plausible DDI occurs when a drug interferes with mals and are extremely expensive to conduct. another, causing irreversible changes to formation Liver slice preparations are of variable ; it of metabolites from one or both. Such suppression is difficult to quantitate the precise stoichiometry or attenuation of metabolism could cause vari- of the oxidant. ances in toxicity and efficacy. iii) Pharmacologists do not know, in advance, the In humans and other animals, most drugs are structure of the metabolites they should seek. metabolised in the liver. Many drug metabolites are iv) Many of the metabolites are not amenable to formed by oxidative mechanisms catalysed primar- organic synthesis by conventional routes. ily by heme and cytochrome-containing enzymes. Most biological oxidations involve primary cataly- Metalloporphyrins as chemical mimics sis provided by the cytochrome P-450 mono-oxy- of cytochrome P-450 systems It will be useful to study metalloporphyrins as mimics of the in vivo metabolic processes. Efficient, sterically-protected and electronically- + 2 + 2 2 activated organic biomimetic catalysts have now been developed. Early synthetic metalloporphyrins )H ,,,SRUSK\ULQ )H ,9 SRUSK\ULQ were found to be oxidatively labile. Few catalytic turnovers were seen due to rapid destruction of the , porphyrin macrocycle. Introduction of halogens on

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to the aryl groups (of meso-tetraarylporphyrins) Advanced Diagnostics and on the ␤-pyrrolic positions of the porphyrins increases the turnover of catalytic reactions by Pharma Assay Services decreasing the rate of porphyrin destruction. The Comprehensive -based gene • A ny mRNA — combined electronegativities of the halogen sub- expression analysis services. stituents are transmitted to the metal making including detection of the oxo-complexes more electron deficient and alternative splice variants and viral-vector more effective catalysts. Conventional catalysts for expressed — oxidation are prone to oxidative dimerisation with are accepted – FFPE, including archival low catalytic turnover numbers (around 5 to 10). • Any tissue all standard tissue preparations These catalysts function with catalytic efficiency reflecting turnover numbers exceeding 100,000. tissues, TMAs, fr — ozen tissue and cell preps Structural scaffolds incorporate the aza macro- cycle into the primary structure. Further structural • Tissue sourcing reliable sources for variants are effected by modulation of the size of • humanBoard-certied and animal tissues macrocycle (number of rings), the substitution pat- tern at the periphery of the aromatic rings, the sub- pathologist review stitution on the internal hydrogens, the metal , the choice of axial ligands, the inorganic counter- • Quantitative image analysis HALO™ Software 20-26 ions and polymers used for immobilisation . • 9,000+ catalog targets available

Diversified analogues through • Two weeks for new probe design automated oxidation chemistry Development and implementation of automated • Four weeks turn-around time from receipt oxidation chemistry to obtain diversified ana- of samples to results for typical projects logues, both as new chemical entities in their own right, and also as substrates for further synthetic conversions, hold significant promise. The oxida- Extensive Experience tion procedure is extremely facile as compared to •10,000+target-specic slides analyzed tissue per expression year biochemical and enzymatic processes. This approach affords an efficient method for the sys- • 500+ tematic preparation and identification of the entire assays validated and successfully performed spectrum of metabolites from a chosen drug. One could take a library and create another library of • 150+ tissue types including normal human, new compounds quite easily and efficiently. preclinical animals, clinical specimens, Relatively low cost as the starting library is already humanized mouse and syngeneic mouse made, and this would provide new compounds tumor models which are more polar, water-soluble and contain handles for further derivatisation. • Eight automated staining systems from Leica Biosystems and Ventana Precision Medicine Medical Systems The pharmaceutical industry assumes that drugs developed and marketed against a disease are ™ indeed effective against the entire patient popula- Introducing BaseScope Assays tion. However, such is not the case since a particu- • Detect and visualize diverse RNA targets lar disease-targeted drug affords clinical efficacy including splice variants, homologous only in a small fraction of that patient . sequences, CAR-T cell clones and more, all The need for translational chemical biology is within the cellular morphological context more than ever in ensuring that the drugs do bring forth therapeutic efficacy to all the patients afflict- ed with that disease; if not, what is it that differen- tiates one patient from the other, and what needs to be done to the drug molecule to be effective against the unresponsive patients? The current modus operandi of modern medicine Learn more at For Research Use Only. Not for diagnosticacdbio.com/pas use. RNAscope is a registered trademark of Advanced Cell Diagnostics, Inc. in the or other countries. All rights Drug Discovery World Winter 2016/17 reserved. ©2016 Advanced Cell Diagnostics, Inc.

Drug Discovery

Figure 6 Oxometalloporphyrins Salient features of catalysts

is based on the determination of an individual’s term ‘personalised medicine’ is also used to convey symptoms, along with an associated diagnosis and this meaning, that term is sometimes misinterpret- subsequent response to a specific treatment as com- ed as implying that unique treatments can be pared to a statistically similar and relevant patient designed for each individual. For this reason, the population dataset or database. The current health- Committee thinks that the term ‘precision care system tends to be reactive providing treatment medicine’ is preferable to ‘personalised medicine’ post-onset of the disease, with limited attempts at to convey the meaning intended in this report. prevention and prediction. All this reliance o n the A Precision Medicine approach utilises individu- comparative analysis of an individual compared to als and defined (sub)-population-based cohorts that a defined population tends to neglect and disregard have a common knowledge network of disease (or human individuality, complexity and variability. It health) . In addition it requires an inte- also fails to recognise the systems level intercon- grated molecular and clinical profile of both the nectedness of human , biochem- individual as well as the sub-population-based istry, metabolism and in the form of sys- cohort. Zhang has described Precision Medicine, tems biology 27. The lack of progress in the effective predicated on the individual patient/sub-population diagnosis and treatment of disease as well as a model as “one-step-up” from the ind ividual patient growing awareness of the complexity and variabili- focus of Personalised Medicine30. Implicit in his ty of individual patients and our limited under- statement is that Personalised Medicine is based on standing of causal mechanisms of onset, and pro- the single individual “N-of-1” model whereas gression of most 21st century diseases, has led to a Precision Medicine uses a “1-in-N” model predicat- growing demand for paradigm change. The clam- ed on widely-used biostatistical data analysis and our for change has led to the emergent growth of ‘big data’ analytical tools. Precision Medicine can ‘P-Medicine’ that includes Personalised and best be described as an amalgam of Personalised Precision Medicine, and a call for more effective Medicine and modern conventional medicine. drug discovery and development process that includes Translational Chemical Biology28. Alzheimer’s Disease – a case study in precision medicine Precision versus Personalised Medicine It was recently suggested that the “...goal of The US National Research Council Report in Precision Medicine is to deliver optimally targeted 201129 attempted to define and differentiate and timed interventions tailored to an individual’s Precision Medicine from Personalised Medicine: molecular drivers of disease”28. As we have Precision Medicine is the tailoring of medical treat- already suggested, the utilisation of Translational ment to the individual characteristics of each Chemical Biology and systems biology tools in this patient. It does not literally mean the creation of type of endeavour is clearly synergistic and can and drugs o r medical devices that are unique to a will facilitate such efforts. However, what specifi- patient, but rather the ability to classify individuals cally can Precision Medicine provide for patients in into subpopulations that differ in their susceptibil- the form of safe and effective therapeutic treat- ity to a particular disease, in the biology and/or ments? We will use the minefield of drug discovery prognosis of those diseases they may develop, or in and development efforts in Alzheimer’s Disease their response to a specific treatment. Preventive or (AD) as a focal point for consideration. therapeutic interventions can then be concentrated The fate of AD drug candidates in the drug on those who will benefit, sparing expense and development process over the past 20 years stands side-effects for those who will not. Although the at a remarkable 99.8% failure rate31. In addition,

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the cost of those failures to the pharmaceutical ii) Identification of potential targets – The net- industry has been in excess of $15 billion for amy- work biology analysis should provide a prioritised loid-␤eta trials alone during that same time period. list of target genes. An assortment of analytical Currently there are 23 Phase I, 47 Phase II and 18 tools primarily employing Phase III AD candidate drugs in US clinical trials. should be used to generate protein expression However, evaluation of the individual clinical trial data, which can be analysed with standard regres- drug candidates reveals that the vast majority is sion techniques, pathway analyses, and structural focused on individual druggable targets in the amy- equation models to provide empirical support for loid-␤eta or tau pathways. Such specific approach- biologic pathways linking proteins to AD es have already proved to be somewhat futile, and endophenotypes. As Bennett notes “the empirical have been compounded by the lack of understand- data will be fed back to the network modelling ing of AD causal onset, as well as the limited appli- stage to refine the network analyses. This compo- cation of Translational Chemical Biology. nent ensures that the candidate genes generated from the systems biology component above are Translational chemical and translated in the and that the mea- systems biology drug discovery sured protein variants themselves are related to The emergence of systems biology in concert with AD endophenotypes”32. the development of a suite of accompanying ana- iii) Functional validation – Utilisation of RNAi lytical and bioinformatics tools and technologies screens to either overexpress or knock down each has facilitated the evaluation and unravelling of of the selected genes in neurons. This provides an complex disease mechanisms27. Therefore it is not efficient, high throughput approach to generating surprising that we and others have suggested such the data required for the analysis of transcriptional an approach should ultimately find widespread use networks. RNA profiles derived from each experi- in understanding causal onset, progression and mental condition will allow the empirical recon- effective treatment of any complex disease such as struction of the molecular networks in the target, AD. Recently we and others have suggested an human cell types to confirm the pathways identi- approach to drug di scovery and development for fied in our initial integrative analyses. This compo- effective and safe AD drugs using a systems biology nent of the pipeline has several purposes: approach31,32. We have argued that any lead drug a) It will refine the networks and confirm that the candidate must disrupt molecular networks genes nominated in systems biology analyses actu- “...that lead to the accumulation of AD neu- ally have the expected effects when they are dis- ropathology and trigger the neurodegenerative rupted on an individual basis. process that leads to cognitive decline and ulti- b) It will identify other genes which may be involved mately to the clinical manifestations of cognitive in the network because they have similar functional impairment and due to AD.” Note the consequences when their expression is perturbed. e mphasis on targeting a network as opposed to a c) It will identify transcriptional programmes or single pathway such as the amyloid-␤eta pathway. ‘gene sets’ that, in vitro, capture aspects of the Based on Bennett’s suggestions as well as our expe- function of a given pathway and can be used as riences we would propose the following broad- outcome measures in future drug screening. based chemical and systems biology approach to d) It will also identify nodal points in each net- drug discovery: work, ‘hubs’ for a given pathway that may make i) Network biology discovery – Multi-omics analy- particularly effective targets for the disruption of a sis at the gene, protein and level. This given cellular pathway. should include DNA methylation, miRNA and iv) Drug candidate screen – Selected prioritised mRNA transcriptomic data from human brain molecular targets that are expressed in the ageing material derived from brain region at the hub of brain and are associated with pathologic and/or neural networks sub-serving cognition, as well as clinical AD quantitative traits, are interrogated AD pathologic and clinical quantitative traits, to with the appropriate chemical or biological library. nominate genes, and therefore proteins, from net- It is important to note that the experimental works and nodes involved in the molecular path- pipeline is by design driven by empiric observations ways leading to AD. We were the first group from the first three stages. This should culminate in responsible for developing a systems biology meth- the selection of target nodal points for molecular ods approach for integrating multi-level ‘omics’ screening which, a priori, were not preselected. data derived from a mammalian system and such Bennett has further suggested that any target approaches are now relatively routine33. should be a nodal point in a network related to AD

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Translational chemical biology – the gap assessment Science, in general, and , specifically, has tended towards in its efforts to solve complex problems. Although this can provide a series of achievable goals, this goes against the reality that biological systems are exactly that, complex systems exhibiting fre- quently unpredictable complex behaviours. We can no more take all the elements in a parts list for a digital camera and, putting them into a box, have the result function like a camera, or having a roster of football players, predict how they will perform in a game. Complexity and systems behaviours are key to enabling function, adapta- tion and survival but they also work against being Figure 7 and a clinically quantitative highly predictable in most instances. Thus a sig- Translation of chemical biology clearly identified by integrative omic data analysis nificant gap will almost always result when towards clinical applications: from human brain tissue. The target must be approaching a problem solely from the bottom- the gap expressed in the brain and also clearly demonstrat- up perspective in terms of predicting true systems ed to be related to AD pathology and clinical phe- function, or in the case of disease, dysfunction… notype. In addition we would argue that any con- while disassembling a complex system does not sideration and scoring of the viability of the target guarantee that each sub-component can be ade- need not simply fit into the amyloid, tau or amy- quately analysed. Optimally, however, a com- loid- tau pathway of AD. We believe that the target bined, iterative approach could provide the best selection criteria should take into account the sys- likelihood for success. tems analysis of the causal onset involving , Currently the rapid development and implemen- amyloid plaque, tau tangles, neurovascular and tation of new technologies, including chemical syn- neuroinflammatory events that occur as a function thesis, has contributed to increasing the size of this of time. gap (Figure 7). This figure emphasises the relation-

Figure 8 The map of valley of death- translational gap

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ship between ‘data’ and ‘information’, ie, ‘data’ that has been cleaned to remove redundancies, and its conversion into ‘knowledge’ and ‘clinical utili- ty’. The process of data generation and cleaning comprise part of the bottom-up approach, but the ability to translate remains to clinical utility com- monly remains elusive because of the lack of under- standing the difference between ‘unmet clinical need’ and ‘unstated, unmet clinical need’. Why does this gap exist and how can we effec- tively close it? As noted earlier, the focus of most efforts in biomedical research have used a ‘bottom- up’ approach, with the development of technolo- gies, where each provides access to a new, but exceedingly narrow, window on biological com- plexity. This leads to a model of the valley of death that includes only discovery, development and reg- ulatory approval (Figure 8)34, but neglects critical Accurate Medicine: Very early in a scientist’s Figure 9 aspects of real world clinical practice and the com- career, the difference between accuracy and preci- Translational gap: Accuracy 37 plexity of real world patients. The result is a limit- sion is taught: “Accuracy is the proximity of mea- versus precision ed potential to close the gap that translates to clin- surement results to the true value; precision is the ical utility. Attempts to overcome these gaps with repeatability, or of the measure- ‘big data’ are also limited by applying a bottom-up ment”37. Precision in a diagnosis, ie the concur- approach because, as W. Edward Deming wrote: rence of multiple clinicians is a laudatory goal “If you do not know how to ask the right question, although not always achievable because of limita- you discover nothing.” One of the first steps in tions in diagnostic guidelines and diagnostic testing framing the right question involves recognising the and individual clinician experience. Accuracy in a incomplete understanding of terms that are being diagnosis can be limited by the reality that patients commonly used to describe these problems, includ- commonly present with syndromes and/or com- ing: translational research, precision medicine, plex disorders that present ambiguity in terms of unmet clinical needs, , pathways, com- signs and symptoms and laboratory results (Figure parative effectiveness, etc. We address below sever- 9) (see diagnosis, below). al of these concepts, but expand the discussion to include the top-down (patient/physician) perspec- Translational medicine: Conventionally, transla- tive and concerns into what has been primarily a tional medicine is defined as a rapidly-growing dis- bottom-up definition. cipline in biomedical research that aims to expedite the discovery of new diagnostic tools and treat- Precision Medicine: It provides an example of the ments by using a multi-disciplinary, highly collab- difference between ‘theory and practice’. The NIH orative ‘bench-to-bedside’ approach38. This goal definition, from the All in Us (formerly Precision has unfortunately met with somewhat limited suc- Medicine Initiative) website discusses “intersection cess as it promotes translation only in one direc- of lifestyle, environment, and genetics to produce tion, thus ignoring the critical issue, as Deming new knowledge with the goal of developing more wrote, of identifying the question first that needs to effective ways to prolong health and treat dis- be addressed. Initiating a ‘bedside-to-bench’ first ease”35 although a more operational definition is step, to identify critical clinical needs presents a “medical care designed to optimise efficiency or higher probability for success transitioning of therapeutic benefit for particular groups of research results into clinical practice. A first step patients, especially by using genetic or molecular involves the critical communication of unmet clin- profiling”36. The two only differ in their apparent ical needs and the even greater appreciation of emphasis on the use of genetic or molecular profil- unstated, unmet clinical needs (see below). ing to accomplish their goals, but neither adequate- ly states the importance of understanding also the Valley of death: As noted in Figure 8, the valley of clinical history of the patient, which rarely con- death conventionally refers to the process involv- tains complete lifestyle and environmental expo- ing progression from discovery to regulatory sure information. approval, costs associated with this process and

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References limited access to adequate funding39. At least two existing conditions and likely concurrent medica- 1 US Food and Drug opportunities exist that can change this dynamic. tions. This will present significant challenges to the Administration. Novel Drugs First, Figure 8 does not adequately include two key development of new preclinical screening methods Summary 2016. considerations that impact potential clinical and and procedures. http://www.fda.gov/Drugs/Dev elopmentApprovalProcess/Dru commercial value, namely, “will the physician pre- gInnovation/ucm534863.htm. scribe the ” and “will the patient take Comparative Effectiveness (CER): CER involves 2 US Food and Drug the medication as prescribed”. Failure to incorpo- direct comparison of existing healthcare interven- Administration. Summary of rate these considerations adequately in early plan- tions to determine which work best for which NDA Approvals and Receipts, ning and evaluation of drug (target) development patients and which pose the greatest benefits and 1938 to the Present http://www.fda.gov/aboutfda/w can lead to clinical (trial) success and approval, at harms. The focus here is, however, on comparative hatwedo/history/productregula great expense, but even greater commercial fail- efficacy44. To truly consider effectiveness of an tion/summaryofndaapprovalsre ures. Second, front-loading investment into better intervention, it is critical to consider if, upon regu- ceipts1938tothepresent/ understanding of the disease process, real world latory approval, a physician will utilise/prescribe default.htm. clinical practice and complexity of real world the intervention, difficulties in being incorporated 3 Woodward, RB. Nobelprize.org. Nobel Media patients and result in more directed, smaller and into profess ional guidelines and whether a patient AB 2014. Web. 16 Jan 2017. shorter clinical trials40. This reduces overall devel- will appropriately follow a physician’s recommen- http://www.nobelprize.org/nob opment cost but, more importantly, can extend the dation. A drug that is highly efficacious but not el_prizes/chemistry/laureates/1 lifetime of the drug for revenue generation under prescribed or taken by the patient is not effective. 965/woodward-lecture.html. patent protection even if the total population may 4 Raut, AA, Chorghade, MS and Vaidya, A. Chapter 4 in be reduced. Biomarkers: There is a tendency to over-utilise Innovative Approaches in Drug biomarkers, as reported in the literature, as surro- Discovery” ed. Bhushan Clinical trial data versus clinical data: Simply put, gates for functional response45. Acceptance without Patwardhan and Rathnam patients who are enrolled in clinical trials, ie meet adequate validation is one problem because of the Chaguturu, . ISBN: 978- the inclusion/exclusion criteria, rarely reflect the noted lack of reproducibility that has become too 0-12-801814-9 (2016). 5 Chorghade, MS, Patwardhan, real world population and are selected to optimise common in the published literature. In addition, the B, Vaidya, A and Joshi, SP. results of efficacy and minimise side-e ffects. It is vast number of published biomarkers presents sig- Current Bioactive well recognised that most patients have multiple nificant challenges to identifying and evaluating the Compounds, 4, 201-212 co-morbid conditions41,47,48 previously treated/ potential value of an individual, or set of, biomark- (2008). currently being treated/as yet undiagnosed as well ers. George Poste, in a frequently misquoted article, 6 Baxendale, IR, Deeley, J, Griffiths-Jones, CM, Ley, SV, as associated poly-, including over-the- wrote that as of 2011, there were 150,000 published Saaby, S, Tranmer, GK. counter products. These real world patients are not articles on biomarkers with less than 100 being used Chemical Communications. 24, typically enrolled in clinical trials yet confront the clinically46. (This is often misquoted as indicating 2566-8 (2006). clinician and impact accuracy in diagnosis and 150,000 biomarkers rather than publications.) We 7 Ley, SV, Sheppard, TD, Myers, response to treatment. Most current diagnost ic and have analysed a subset of only the oncology litera- RM and Chorghade, MS. Bull.Chem.Soc., Japan, 82, (8), treatment guidelines, however, do not adequately ture and found that there were 42,440 studies for 1451-1472 (2007). incorporate these factors in their development. which 38,426 biomarkers were observed. Of these, 8 Lushington, GH, Guo, JX, 24 were EMEA approved, 30 were FDA approved, Wang, JL. Curr Med Chem. 14: Drug safety: Drug safety is typically considered in where 23 were approved by both agencies. Of these, 1863-1877 (2007). preclinical studies and focuses on dosing, toxicolo- a very limited subset has proven to be commercially 9 Murphy, RF. Nat Chem Biol. 42 47 7: 327-330 (2011). gy and potential for notable side-effects . successful . The enhanced sensitivity of new ana- 10 Dressman, JB, Thelen, K, Ongoing debate exists about the use and adequacy lytic methods will require significant advances in the Willmann, S. Expert Opin Drug of animal testing models in reflecting human processes for validation. Even diagnostic Metab Toxicol. 7: 1345-1364 response and significant failure of these models to test results can be misleading, particularly when dif- (2011). replicate human response is widely known. New ferent methods are used to measure the same mark- 11 Berellini, G, Springer, C, Waters, NJ, Lombardo, FJ. Med. testing paradigms are a major area of development er. For HER2/neu determination in breast , Chem. 2009; 52: 4488-4495 including stem cells and also integration of compu- both IHC (immune-histochemistry) and FISH (fluo- (2009). tational modelling of systems biology. Of note, rescent in situ hybridisation) are approved, but one 12 Liu, H, Wang, L, Lv, M, Pei, R, however, is the increasing interest in potentially measures protein expression levels and the other Li, P, Pei, Z, Wang, Y, Su, W, Xie, accelerating the administration of drugs, post-safe- measures gene copy number. These processes are not X-Q. J Chem Inf Model. 54: 1050–1060 (2014). ty evaluation, into humans rather than following equivalent and in large studies where both tests are 13 He, YY, Liew, CY, Sharma, current regulatory procedures43. It will be critical administered, approximately 22% discordance N, Woo, SK, Chau, YT, Yap, CW. to consider how to enhance safety screening to exists41. A common limitation in current transla- Journal of Computational incorporate aspects of precision medicine that tional research is using biomarkers as targets when Chemistry. 34: 604-610 (2013). should consider heterogeneity in the target popula- they only show correlative relationship to disease, Continued on page 87 tion and differences in diagnostic guidelines, pre- not causal.

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Co-morbidities: As noted above, real world may start at the time of disease diagnosis and com- Continued from page 86 patients rarely present with a single, isolated dis- munication with the physician, patient’s perception ease but with co-morbid conditions that may have of risk of disease versus risk from , 14 Douglas, EV. Pires, DEV, Blundell, TL, Ascher, DB. 58: been treated (under management), concurrent or as patient preferences and concerns about impact on 4066-4072 (2015). yet undiagnosed. In addition, each patient is deal- lifestyle factors, eg impotency, appearance, eg acne, 15 Shimpi, SL, Mahadik, KR, ing with a poly-pharmacy situation that may etc. These observations should emphasise the need Paradkar, AR. 57: 937-942 extend to 15 medications, plus over-the-counter to include psycho-social and cultural factors into (2009). and dietary treatments, as well as variability in models that represent patient progression through 16 Bergström, CAS, Charman, WN. Porter, CJH. Advanced adherence to prescribed dosing48,49. This com- the entire disease process and interaction with the Drug Delivery Reviews. 2016; plexity, as we have observed, is apparent in the healthcare . 101: 6-21 (2016). analysis of nationalised healthcare data, ie a uni- 17 Young, DM. The Toxicity fied patient-based health record, and reflects the Diagnosis: As noted above, accuracy in diagnosis Estimation Software Tool reality that physicians may not fully utilise such is critical and also potentially one of the most crit- (T.E.S.T.). Presented at New data because of the limitations in existing guide- ical factors in patient management… and success- Networking Forum, , lines, their personal experience and/or patient pres- ful development of new drugs and interventions. MA, December 16, 2010. sure. The impact on quality of diagnosis, response Physician evaluation of a patient needs to establish 18 Patlew icz, G, Jeliazkova, N, to clinical testing and to treatment can be readily a more accurate diagnosis than currently available Safford, RJ, Worth, AP, Aleksiev, appreciated but reflect limitations when attempt- in terms of disease stratification (or subtyping B. Environ Res. 19: 495-524 (2008). ing to apply highly refined molecular methods to based on temporal presentation) by evaluating 19 He, J, Leung, RK, Li, Z, diagnose or assess individual patients. progression of multiple clinical parameters over Cheng, R, Chen, Y, Pan, Y, Ning, time, determining how far along this complex dis- L. Virtual . 2016; Compliance: Compliance considers the clinician’s ease trajectory a patient has progressed, ie their available online at: tendency to follow established clinical guidelines disease stage, and how quickly they are progress- http://www.sustc- genome.org.cn/vp/. and protocols. Guidelines are frequently developed ing, ie disease velocity. A late-stage, slow-moving 20 Andersen, KE, Begtrup, M, by professional societies but rarely consider the disease may be treated very differently from one Chorghade, MS, Lau, L, Lee, complexity of real patients in terms of likely co- exhibiting early stage, aggressive progression. EC, Lundt,BF, Petersen, H, morbid conditions and medications except those These factors are of particular value in dealing Sorensen, PO and Thogersen, that have been noted to present significant side- with current diagnoses involving syndromes H. Tetrahedron, 50 (29), 8699 (1994) Erratum cited in effects and contraindications. Since randomised rather than specific diseases41. Tetrahedro n, 52 (10), 3375 clinical trials are considered the highest level of evi- (1996). (ii) Celebuski, JE, dence for the development of evidence-based Disease state versus disease trajectory: As noted Chorghade, MS and Lee, EC. guidelines, it should be noted that typical inclu- above, disease is a process that evolves over time, Tetrahedron Lett.35 (23), 3837 sion/exclusion criteria limit the presence of co-mor- other than the initial impact of trauma, and needs (1994). Corrigendum published in Tetrahedron Lett. 36 (52), bid conditions and many additional drugs that a to incorporate temporal processes to better diag- 9414 (1995). patient may be taking. Separately, many guidelines nose and manage outcomes. In addition, in 21 Andersen, JV, Chorghade, are developed as ‘consensus guidelines’ and thus chronic diseases, eg diabetes and Alzheimer’s, it is MS, Dezaro, DA, Dolphin, DH, not be uniformly consistent in their quality and critical to recognise that the patient will be under- Hill, DR, Lee, EC, Hansen, KT support, by the developers, across their multiple going physiological changes in normal develop- and Pariza, RJ. Bioorganic and Medicinal Chemistry Letters, elements of decision support. And finally, physi- ment throughout the disease course and it may be 1994, 4 (24), 2867 (1994). cians recognise that with such deficiencies, guide- critical to deconvolute the influences of each to be 22 Chorghade, MS, Dolphin, lines are only guidelines and frequently practice able to provide for the best diagnosis, treatment DH, Hill, DR, Hino, F, Lee, EC, based on personal and personally-shared experi- and outcome51. Zhang, L-Y and Pariza, RJ. Pure ence, eg off-label prescribing. and Appl. Chem., 68 (3), 753 (1996). Unmet clinical need/unstated unmet clinical need: 23 Hill, DR, Celebuski, JE, Adherence: Patient adherence to prescribed While it is obvious that fundamental (and discov- Pariza,RJ, Chorghade, MS, drug/treatment regimes is acknowledged to cost at ery) research can best impact healthcare by Levenberg, M, Pagano, T, Cleary, least US$300 billion annually in the US because of addressing unmet clinical need, it is important to G, West, P and Whittern, D. failures in adequate disease management and the understand how to identify and validate that Tetrahedron Lett. 37 (6), 787 (1996). need for hospital readmission50. In addition, there need41. The current pressures and practices in 24 Chorghade, MS, Dolphin, is loss of prescription value to pharma and healthcare present the clinician with little opportu- DH, Dupre, D, Hill, DR, Lee, biotechs. Most efforts to improve adherence focus nity to explore the needs of their practice much EC and Wijesekara, TP. on monitoring patient behaviour post prescription- beyond what addresses daily operational issues. Synthesis 1320 (1996). filling and/or reminders and counselling. These This challenge is amplified with both the rapid attempts to apply technology may miss the critical development and commercialisation of new tech- issue involving individual patient behaviours that nologies for diagnosis and treatment as well as Continued on page 89

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Figure 10 Holistic view of translational chemical biology principles: A pyramidal foundation of human medicinal health, based on chemical biology and elaborated via enabling technologies and protocols. Concave arrowheads show the prevailing direction of translational information flow. White arrows indicate traditional areas of strong knowledge feedback which foster alternative translational opportunities

exploding, and frequently inadequately vetted, Concluding remarks generation of research publications. As Henry Ford We have tried here to initiate discussion about the wrote: “If I had asked my customers what they complexities that face drug development, patient wanted, they would have said a faster horse.” In management and healthcare beyond their current initiating research into the development of new horizons. It presents a perspective that current solutions to clinical problems, it is critical to go basic research could benefit from understanding beyond that simple question of “what do you the reality of the multiple, hierarchical systems that need?” In extension to the discussion about impact the translation of laboratory results into Her2/neu testing mentioned above, we can exam- utility and clinical practice. These systems operate ine triple negative breast cancer where HER2, ER at the molecular, personal, society and population and PR testing produces negative results52. levels, but do not function independently of their Variability in HER2 testing was noted, but also dif- interactions across these levels54. ferences in ER and PR testing exists, along with the We propose innovative that variation among hospitals/laboratories in estab- addresses the general need for improved com- lishing threshold values for +/- in such tests. While pound diversity for a variety of applications in bio- it might be expected that three negative tests would science, and translational chemical biology The be an easy discriminator for est ablishing a diagno- approach applies a combination of natural product sis, this is not the case, and may naturally interfere isolation, synthesis, diversification, automated with additional testing and analysis that relies on purification and structure analysis. Such pro- consistency of that diagnosis. And while it might grammes can draw upon the highly complemen- be suggested that further genomic and/or molecu- tary expertise and resources of leading academic lar markers, observed in tissue, could enhance the and industrial research teams. diagnosis and potential stratification, it is worth From foundation to capstone, any translational noting that significant heterogeneity has been endeavour exemplifies a pyramidal enterprise. In observed and classified in breast cancer tissue, all cases, an extensive knowledgebase yields a nar- yielding discernible patterns that can confound the rower subset of opportunities that are subsequent- conventional diagnoses, and more recently, have ly honed and winnowed down to a single critical been associated with the high degree of variability new capability. This structure applies regardless of in patient response to targeted therapeutics53. whether one is translating from general scientific

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understanding to broader health principles, from in several national and international conferences. Continued from page 87 specialised chemical biology to a specific new drug, He has been honoured by election as a Fellow to or beyond this from patient-specific omics data the Maharashtra, Andhra Pradesh and Telengana 25 Chorghade, MS*(Editor) and Lee, EC (Associate toward precision medicine, or from broad health Academy of Sciences, Royal Society of Chemistry, Editor), Pure and Appl. Chem., records toward optimal medical outcomes. New York Academy of Sciences, American 1998, 70 (2), Proceedings of While we can appreciate how translational Chemical Society, American Institute of Chemists, the XXth IUPAC Symposium chemical biology will contribute to improving AAAS, Sigma Xi, Indian Society of Chemists and on the Chemistry of Natural patient management and reducing healthcare costs . Products, Chicago, September, preface page vi (1996). in the short-term, we believe that only through the 26 Chorghade, MS. development and evaluation of models of the true Dr Michael Liebman is the Managing Director of Metalloporphyrins as Synthetic complexity of the healthcare ecosystem, real world IPQ Analytics, LLC and Strategic Medicine, Inc Livers, published in Drug clinical practice and real world patients, will long- after serving as the Executive Director of the Metabolism: Databases and term benefits be realised. Again, correlation does Windber Research Institute from 2003-07. Michael High Throughput Testing during and not infer causality, and modelling cause and effect is Chair of the Informatics Program and also Chair Development, International will be required to create new systems for research, of Translational Medicine and Therapeutics for the Union of Pure and Applied translation and delivery of improved healthcare. PhRMA Foundation. He serves on several scientific Chemistry: DMDB Working We need to also understand t hat simply asking a advisory boards including the International Society Party, Ed. Erhardt, PW. clinician what they need will not necessarily result for Translational Medicine and on the Editorial Blackwell pp.152-162 (1999). 27 Naylor, S and Chen, JY. in understanding what the real need may be. Board for the Journal of Translational Medicine, Personal. Med. 7; 275-289 Physicians are accustomed to working with what for Clinical and Translational Medicine and for (2010). they have to address critical issues on a daily basis Molecular Medicine and Therapeutics, for Clinico- 28 Naylor, SJ. Precision Med. 2; and not on exploring either the limitations that Economics and Outcomes Research and 15-29 (2015). may exist or the potential for developing new Biomedicine Hub, and the International Park for 29 US National Research Council. US National approaches. To really understand unmet clinical Translational Biomedicine (Shanghai). His research Academies Press, Washington need requires an immersion in observing and mod- focuses on computational models of disease pro- DC USA (2011). elling the clinical process. These models can serve gression that stress risk detection, disease processes http://www.nap.edu/catalog/13 as the basis for asking more directed questions and and clinical pathway modelling, and disease strati- 284/toward-precision- gaining the confidence and access to the experience fication from the clinical perspective. He utilises medicine-building-a- knowledge-network-for- of the physician in revealing their perceptions systems-based approaches and design thinking to biomedical-research. about what really works and what does not. represent and analyse risk/benefit analysis in phar- 30 Zhang, XD. maceutical development and healthcare. & Acknowledgements Pharmacoproteomics 2015; 6; We thank our many colleagues who have influenced Dr Gerald Lushington, an avid collaborator, e14 doi: 10,4172/2153-0645. 1000e144. us in innumerable ways over the years and for being focuses primarily on applying simulations, visuali- 31 Waring, SC and Naylor, SJ. the beneficiary of their collective wisdom. DDW sation and data analysis techniques to help extract Precision Med. 5; 38-53 (2016). physiological insight from data, 32 Bennett, DA, Yu, L and De and relate physical attributes of small bioactive Jager, PL. Biochem. Pharmacol. Dr Mukund Chorghade is a serial entrepreneur, molecules (drugs, metabolites, toxins) toward 88: 617-630 (2014). 33 Clish, C, Davidov, E, Oresic, President and Chief Scientific Officer of THINQ physiological effects. Most of his 150+ publica- M et al. OMICS 8:3-13 (2004). Pharma/THINQ Discovery. He has had Adjunct tions have involved work with experimental 34 http://www.fastercures.org/ Research Professor/Visiting Fellow/Scientists molecular and biomedical scientists, covering newsroom/newsroom/. appointments at Harvard, MIT, Princeton, diverse pharmaceutical and biotechnology applica- 35 https://www.nih.gov/ Cambridge, Caltech, University of Chicago, tions. His technical expertise includes QSAR, research-training/allofus- research-program. Northwestern and Strathclyde. He directed quantum and classical simulations, statistical mod- 36 Precision Medicine, Wikipedia. research groups at Dow Chemicals, Abbott, elling and machine learning. Key interests include 37 Precision vs Accuracy, CytoMed and Genzyme. His current research inter- applying simulations and artificial intelligence to Wikipedia. ests are in Traditional Medicine-derived New extract. After productive academic service, 38Wang, X. Clinical and Chemical Entities and the discovery of the new Lushington’s consultancy practice supports R&D Translational Medicine, 1:5 (2012). 39 https://www.slas.org/eln/ ‘chemosynthetic livers’ with utility in drug and commercialisation efforts for clients in bridging-the-valley-of-death- metabolism, valorisation of biomass and environ- academia, government and the pharmaceutical and how-can-academia-and- mental remediation. Dr Chorghade received his biotechnology industries. Dr Lushington serves as pharma-best-work-together/. PhD at Georgetown University, with postdoctoral Editor-in-Chief of the journal Combinatorial 40 PharmaFocus Asia, 9, 1-8 appointments at the University of Virginia and Chemistry & High Throughput Screening, (2008). Harvard University. A recipient of three ‘Scientist Bioinformatics Editor for Web – MedCentral and of the Year Awards’, he has been a featured speaker is on editorial boards for Current Bioactive Continued on page 90

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Continued from page 89 Compounds, Current Enzymology and the Journal need for innovation and entrepreneurship and the 41 Liebman, MN, Franchini, M of Clinical Bioinformatics. virtues of collaborative partnerships in addressing and Molinaro, S. Technology the pharmaceutical innovation crisis, and aggres- and Healthcare vol. 23, no. 1, Dr Stephen Naylor is the Founder and CEO of sively warns the threat of scientific misconduct in pp. 109-118, (2015). 42 Pre-clinical studies, Wikipedia. ReNeuroGen LLC, a virtual pharmaceutical com- biomedical sciences. He received his PhD with an 43 Kaplan, S. Winners and pany developing precision medicine therapies for award-winning thesis from Sri Venkateswara losers of the 21st Century the treatment of stroke. In addition he is the University, Tirupati, India. Correspondence can be Cures Act. STAT News. (5 Founder, Chairman and CEO of MaiHealth Inc, a addressed to him at [email protected] December 2016). systems/network biology level diagnostics compa- 44 http://effectivehealthcare. ahrq.gov/index.cfm/what-is- ny in the health/wellness and precision medicine comparative-effectiveness- sector. He was also the Founder, CEO and research1/. Chairman of Predictive Physiology & Medicine 45 Barker, M. Nature, 533, (PPM) Inc, one of the world’s first personalised 452-454 (2016). medicine companies. He serves also as an Advisory 46 Poste, G. Nature, vol 469, p156-157 (2011). Board Member of CureHunter Inc, a computation- 47 Liebman, MN. In al biology drug discovery company, and as a busi- collaboration with Excelra, ness adviser to the not-for-profit Cures Within unpublished results. Reach. In the past he has held professorial chairs in 48 Braithwaite, D, Tammemagi, Biochemistry & Molecular Biology; CM, Moore, DH, Ozanne, EM, Hiatt RA, Belkora, J, West, DW, Pharmacology; and Satariano, WA, Liebman, M, Biomedical , all at Mayo Clinic in Esserman, L. Int J Cancer. Mar Rochester, MN, USA. He holds a PhD from the 1;124(5):1213-9 (2009). University of Cambridge (UK), and undertook a 49 Franchini, M, Pieroni, S, NIH funded fellowship at MIT located in the Fortunato, L, Molinaro, S and Liebman, MN. Current ‘other’ Cambridge, USA. Pharmaceutical Design, Volume 21, Number 6, pp. 791-805(15) Dr Rathnam Chaguturu is the Innovation Czar, (February 2015). Founder & CEO of iDDPartners (Princeton 50 Iuga, AO and McGuire, MJ. Junction, NJ, USA), a non-profit think-tank Risk Management and Healthcare Policy, 7, 35-44 (2014). focused on pharmaceutical innovati on, and most 51 Franchini, M, Pieroni, S, recently, Deputy Site Head, Center for Advanced Fortunato, L, Knezevic, T, Drug Research, SRI International. He has more Liebman, MN and Molinaro, S. than 35 years of experience in academia and indus- Clinical Translational Medicine try, managing new lead discovery projects and 5:24 1-13 (2016). 52 http://www.medscape.com/ forging collaborative partnerships with academia, viewarticle/822516. disease foundations, non-profits and government 53 Maskery, S, Zhang, Y, Jordan, agencies. He is the Founding President of the R, Hu, H. Hooke, J, Shriver, C International Chemical Biology Society, a and Liebman, M. IEEE Founding Member of the Society for Biomolecular Transactions on Information Technology in Biomedicine, 10, Sciences and Editor-in-Chief-Emeritus of the jour- 3, 497-503 (2006). nal Combinatorial Chemistry & High Throughput 54 Liebman, MN. Translational Screening. Rathnam passionately advocates the Scientist, 2701-2705 (2016).

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