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Perspe ct ive on when multi-t arge ting is adva ntageous

The safety and efficacy of therapeutic drugs still requires improvement. In part this is due to the promiscuity of individual drugs, which on average can interact with an estimated 6-28 other off-target moieties. However, the advent of both systems and has stimulated a rethink on the process of therapeutic and polypharmacology. More recently, the definition of polypharmacology has morphed to represent therapeutic drugs that have been designed deliberately for multi-targeting that affords beneficial effects to the patient. This emerging effort has been labelled ‘Systems Pharmacology’ and the products are referred to as multi-target or systems pharmacology drugs.

he current Drug Discovery and Develop- The metrics associated with the DDD process By Dr Kirkwood A. ment (DDD) was conceived in the are clearly problematic. There is also a concern Pritchard Jr, Tearly 1960s and has remained relatively about the safety and efficacy value proposition of Dr Dustin P. Martin unchanged over the past ~60 years. We, and others, current marketed therapeutic drug products pro - and Dr Stephen have argued that this continues to be a risk-laden, duced by the current DDD process. In part this is Naylor slow, costly and inefficient process, as well as deliv - due to: ering products of questionable value in terms of safety/toxicity and efficacy 1-5 . For example, signifi - i) Drug safety: Not all approved drugs stand the cant cumulative risk is associated with any effort to test of market pressures due to the scrutiny of bring a candidate drug to market. The initial pharmacovigiliance and post-market surveillance. screening of compound libraries (10 4-10 6 candi - In some cases approved drugs can be removed dates), leads to a single lead compound that has from the market because they manifest safety, only an ~8% chance of successfully traversing the effectiveness or economic problems. For example clinical trials gauntlet 6. In addition, the failure rate from 1994-2015, the USA Food and Drug of a drug candidate at each clinical trial phase is Administration (FDA) issued 215 ‘Withdrawal of reported to be 46% (Phase I), 66% (Phase II) and Application’ notices 8. During that same time peri - 30% (Phase III) 4. The average time required from od the FDA actually recalled 26 drugs from the US drug discovery to product launch remains an eye- market predicated primarily on safety concerns 9. watering 12-15 years 5. In addition, the total capi - talised cost of bringing a new drug to market was ii) Drug effectiveness: There is now a significant recently estimated at a staggering $2.87 billion 7. body of evidence that indicates individual patients

Drug Discovery World Winter 2018/19 33 Systems Pharmacology

Figure 1 Schematic representation of therapeutic drug effect on individual . In the one drug-one target model the health of an individual was determined, in many cases, by a single diagnostic indicator such as blood glucose levels in diabetic patients. A patient was determined to be healthy if the diagnostic value was within a range limit (Healthy – black line represents the range). As disease onset and progression occurred the individual’s body was determined to be out of homeostasis (Diseased). However, disease severity was still determined by one diagnostic marker. Application of a therapeutic drug, which theoretically only interacted with a single target, should move the individual back into homeostasis. If the drug interacted with an ‘off-target’ then the condition of the patient could deteriorate (Adverse). In the case of a one drug-multi-target- pathway/network drug of diagnosed with the same disease indication drugs 17 , particularly in the treatment of systems pharmacology, the respond differently to the same therapeutic drug 10 . Alzheimer’s disease 19 . In addition, we have sug - fundamental homeostatic For example, Spears and co-workers analysed the gested that the development of precision medicine model still applies, however 2 instead of a one-dimensional effectiveness of a number of different drug classes drugs , as well as an integrated technology plat - diagnostic range and limited against major disease indications 11 . They found form-DDD approach 3 may also facilitate improved efficacy effect, there is a more that most drugs were ~30-75% effective as deter - drug pipeline products. In this manuscript we dis - comprehensive data rich mined by patient responses. The lowest responders cuss drug polypharmacology, which has usually definition of a homeostatic were oncology patients treated with conventional been equated with therapeutic drug-target promis - ‘circle’ Such an approach leads to a more efficacious cancer chemotherapy agents (25% of patients cuity, resulting in safety/toxicological side-effects treatment and minimisation of responded positively). In contrast, the highest per - and reduced efficacy 20,21 . More recently, the term toxicity, safety and side-effects centage of patient responders resulted from treat - has been used to describe the benefits of a single ment with Cox-2-inhibitors (80%). Therapeutic drug affecting change at multiple targets (one drug- drugs were reported to be ineffective for multi-targets) for more efficacious impact of the Alzheimer’s (70%), arthritis (50%), diabetes drug predicated on systems biology and precision (43%) and asthma (40%) patients 11 . medicine considerations 22 . All this is considered and discussed as well as the emerging paradigm of We have argued in the past that the ‘Blockbuster systems pharmacology 23 . Model’ has inadvertently led to the ‘wagon-of- woe’ for the DDD process 12 . This approach Human complexity, systems utilised the ‘one drug-one target’ model that was biology and precision medicine relatively effective in large, poorly-defined, hetero - The original ‘one-drug-one target’ model was geneous patient . We have suggested predicated on a rather simplistic perspective of the integrated use of more efficient technologies 13 , human and . The health of an decision-making tools 13 , systems biology 14,15 and individual was determined by a number of diag - personalised/precision medicine 16-18 in order to nostic markers such as blood glucose levels. When overcome the limitations of such a model. We have the concentration levels of such a marker changed presented the concept of systems biology-person - beyond a certain defined clinical range then the alised/precision medicine approaches for the pro - patient was diagnosed with a specific disease indi - duction of more effective and safe therapeutic cation (see Figure 1 for a schematic representation

34 Drug Discovery World Winter 2018/19 Systems Pharmacology

of this process). Administration of a single drug fied , more than 100 million antibodies and that modulated a specific target changed the con - ~40,000 . The combined length of DNA centration of the diagnostic marker back to a nor - in an individual is calculated at approximately 2 x mal range value, reverting the individual’s patho - 10 13 meters, which is the equivalent of 70 round biological state to healthy status. However, with trips between the earth and the sun. We estimate the advent of systems biology and a new paradigm also that the total number of chemical reactions/ driven by precision medicine, a greater under - interactions occurring in a single individual is ~3.2 standing of human complexity emerged, concomi - x 10 25 per day! This exceedingly large number is tant with a re-evaluation of the ‘one drug-one tar - actually greater than the number of grains of sand get’ paradigm 17 . estimated to be present on the entire planet, which has been calculated at 7.5 x 10 18 grains 18 . Human complexity and variability A further layer of complexity is that an individ - In the past, our understanding and appreciation of ual human is obviously not a closed . On a human complexity and variability at the cellular, daily basis each one of us requires inputs as well as individual and level has constantly outputs. For example, we consume on average been constrained by lack of adequate analytical, ~1.27kg/day of food and drink (if you are follow - bioinformatic and knowledge management tech - ing current healthy living advice) ~6-8 litres/day of nologies. In addition our comprehension of the fluid. It is also thought-provoking to consider that dynamic of human and physiol - more than 25,000 bioactive food and beverage ogy as a of time was also extremely limit - components have been identified. At any one time ed. Furthermore, diagnosis, prognosis and treat - in the consumption of a normal meal, an individu - ment decisions had been driven by a reductionist al may consume several thousand individual bioac - approach, which led to the development of rela - tive chemicals. In addition we plaster on to our tively simple physiological models, as well as a bodies ~100-500 cosmetic ingredients on a daily rudimentary and incomplete understanding of basis. In terms of output, we lose six litres of complex biological processes occurring in individ - fluid/day via urination, which contains ~3,000 uals. This has all resulted in a limited ability to active chemical constituents. We also remove on make unambiguous and decisive decisions about average ~350-500g of solid waste products optimal therapeutic drug treatments for individual through defecation on a daily basis and up to six patients 17 . litres of sweat depending on physical exertion. All It is salutary to consider the dynamic complexity of this activity is mediated by a transport system and variability of an individual human patient 17,18 . consisting of ~100,000 kilometers of arteries, veins For example, at the cellular level a single human and capillaries moving approximately five litres of is made up of ~100 trillion water , ~20 blood and lymph fluid throughout the body. It is billion proteins, ~850 billion fat molecules, ~5 tril - interesting to put all this into context and consider lion sugars and amino acids, ~1.5 trillion inorganic that a modern miracle of technology, the beloved moieties, ~50 million RNA molecules and 2 meters Boeing 747 aircraft, has only six million parts and of DNA within 23 pairs of chromosomes. We esti - a mere 285km of wiring or tubing. Is it reasonable mate, based on the requirements of individ - to wonder aloud why we struggle with accurate ual cells in the form of adenosine triphosphate prognosis, diagnosis, and treatment or indeed as to (ATP) turnover, there are ~860 billion chemical why we actually function at all 18 ? reactions/interactions performed per day in a single We have previously discussed that it is possible cell! At the individual level, a single human being to quantify human complexity 17 , but in the case consists of ~37.2 trillion cells, made up of 210 dif - of human variability we are confounded by the ferent cell types, and 78 organs/ systems. In range and subtlety of these differences. Such traits addition, each one of us hosts ~100-300 trillion can be transitory or permanent and influenced in microbes, composed of ~10,000 different species complex ways by both genetic and/or environmen - that constitute 1-3% of our body weight and con - tal factors. Sources of human variability include tain an estimated 8 million -coding genes. gene (germ-line and somatic), allelic dif - These micro- play an intimate and inter - ferences, , social and cultural influ - woven role in the health and pathobiology of the ences and . Common human variations human host. The molecular machinery of the include obvious visible differences such as gender, comprises ~19,000 coding genes, age and physical appearance. These differences are ~20,000 gene-coded proteins and 250,000-1 mil - determined through poorly-understood molecular lion splice variants and post-translationally modi - processes. Such processes are modulated by a wide

Drug Discovery World Winter 2018/19 35 Systems Pharmacology

Table 1: Comparison of sub-systems in humans. Analysis of the distance (in metres) between individual constituents of each sub-system as well as the average timescale that interactions and reactions occur

SUB-SYSTEM TYPE DISTANCE (METRES) AVERAGE TIMESCALE (HUMAN) (SECONDS)

Molecular ~2x10 -8 - ~5x10 -10 10 -6

Pathway/Network ~1x10 -6 - ~3x10 -8 10 2

Cell ~1x10 -4 - ~8x10 -6 10 4

Tissue ~2x10 -2 - ~9x10 -4 10 5

Organism ~6x10 -1 - ~(1-2) 10 6 - 10 8

variety of molecular entities and processes that predicated on theoretical considerations of complex include, but are not restricted to, single nucleotide systems analyses. Second generation systems biolo - polymorphisms (SNPs), alternative genesplicing gy (late 1990s-early 2000s) has its roots in high and protein isoforms (eg cytochrome P-450 super throughput analytical omic measurements, bioin - family) and epigenetic phenomena. Our basic formatics, bioengineering, computational sciences understanding of these processes have led to the and . It is an attempt to establish a creation of simple semantic descriptors which more integrated and hierarchical paradigm that define such differences and include concepts such facilitates the creation of new biological pathways as gender, age differentiation (child versus adult) and networks at the molecular and cellular level 15 . and race. However, such coarse descriptions do This provides a framework for understanding the not provide adequate insight into the significant holistic system of genetic, genomic, transcriptomic, and subtle differences that separate us at the protein, and cellular events that are in molecular level, given that ALL humans are constant flux and interdependent. In order to facil - 99.9% genetically the same at the DNA level 18 . itate such efforts, two distinct approaches have Finally, the temporal effect on complexity and evolved, namely computational modelling-based variability is an even poorer-understood process. systems biology and data-driven systems biology. Paradoxically, age is the most obvious manifesta - The former relies primarily on computational mod - tion of physical change in the individual. We can elling and simulation tools. While there has been all recognise the phenotypical differences between some confusion in the past about terminology it is infants versus a young girl/boy versus an elderly also now referred to ‘bottom-up’ systems biology. woman/man. Also it is ‘well-known’ that we lose The latter approach predominantly utilises analyti - bone density, shrink and our metabolism slows cal datasets that are mined in a discovery manner down. However, our understanding of individual for new knowledge using a variety of bioinformat - or population changes at the molecular and cellu - ics and knowledge assembly tools and is now cate - lar levels is still in its infancy. In the past, our gorised as ‘top-down’ systems biology 17 . understanding of this staggering, dynamic com - plexity and variability has been myopic and limit - Implementation of Systems biology in DDD ed. Hence, how can we produce safe and effica - We opined back in 2004 that systems biology could cious therapeutic drugs for individual patients 18 ? “…provide a new dynamic to invigorate pharma - ceutical companies… predicated on a more com - Systems biology plete understanding of problems associated with The of systems biology (also known as the DDD process” 15 . A consensus emerged that pathway, network or integrative biology) was pre - systems biology had the potential to impact the dicted on an attempt to address and embrace entire DDD process by identifying biological sub- human complexity and variability in human systems and how they interact to produce complex metabolism, physiology and pathobiology. The molecular, pathway/network, cellular, and development of systems biology is still in its nascent behaviour 23,24 . Such claims appear ascendency. In its first generational incarnation extraordinary when you consider the complexity (1940s-50s), a systems approach to biology was and variability of both individuals as well as differ -

36 Drug Discovery World Winter 2018/19 Systems Pharmacology

ent human sub-populations (see section above). In for the near future. In comparison, systems biology References addition the difference in molecular, pathway/net - has had a much greater impact on the of 1a Naylor, S and Schonfeld JM. work, cellular, tissue and organism reaction time - precision medicine over the past decade 17-19,27 . Therapeutic Drug Repurposing, Repositioning, frames and proximal distances is dramatic (see and Rescue: Part I- Overview. Table 1 ) and attempts to integrate all such process - Precision medicine Drug Discov. World. 2014; es appears exceedingly difficult. However, in spite We described recently, in some detail, the advent of Winter Edition, 49-62 (2014). of these daunting obstacles there has been a great precision medicine drugs 2. The development of 1b Kauppi, DM and Naylor, S. deal of activity in the application of systems biology such therapeutic agents is a continuing and realistic Therapeutic Drug Repurposing, Repositioning to the DDD process, and a number of books have attempt to improve the efficacy of therapeutic and Rescue: Part IV- Financial 25 been written on the subject . But, to date, the drugs by treating targeted patient sub-populations. Model and Analysis. Drug effect of systems biology on DDD has been some - The term ‘precision medicine’ was first coined by Discov. World. Winter Edition, what underwhelming because of interpretation and Clayton Christensen in his book the Innovator’s 54-63 (2016). utilisation difficulties with the data and informa - Prescription published in 2009 29 . However, the 2 Kiernan, UK and Naylor, S. Precision Medicine Drugs: tion obtained on specific biological sub-system or descriptor ‘precision medicine’ did not gain wide Pleonasm or Reality? Drug system perturbations. acceptance and usage until a report entitled Discov. World. Summer Due to the aforementioned limitations, systems ‘Toward Precision Medicine: Building a Edition, 9-16 (2018). biology has only provided notable insights into: Knowledge Network for Biomedical Research and 3 Kiernan, UK and Naylor, S. i) drug-target networks; ii) predictions of drug-tar - a New of Disease’ was published by the Emerging Paradigm of Integrated Platform-Drug get interactions; iii) adverse drug effects of drugs; US National Research Council (NRC) in 2011 30 . Discovery and Development iv) drug repositioning; and v) predictions of drug The report stated: “Precision medicine is the tailor - Companies. Drug Discov. combination 25,26 . There are continued efforts to ing of medical treatment to the individual charac - World. Fall Edition, 33-43, broaden the applicability of systems biology to the teristics of each patient. It does not literally mean (2018). DDD process. For example, recently we and others the creation of drugs or medical devices that are 4 Paul, SM et al. How to Improve R&D Productivity: the have suggested a systems biology approach to pro - unique to a patient, but rather the ability to classify Pharmaceutical Industry’s vide an understanding of causal onset, progression individuals into subpopulations that differ in their Grand Challenge. Nature and effective treatment of any disease, including susceptibility to a particular disease, in the biology Reviews: Drug Discovery, 9, complex disease states such as Type II diabetes 27 and/or prognosis of those diseases they may devel - 203-214 (2010). and Alzheimer’s Disease 19,28 . We have proposed op, or in their response to a specific treatment. 5 Deloitte Centre for Health solutions. Measuring the the following broad-based systems biology Preventive or therapeutic interventions can then be Return from Pharmaceutical 19 approach to drug discovery : concentrated on those who will benefit, sparing Innovation Turning a Corner? expense and side-effects for those who will not” 30 . (2014). http://www2.deloitte. i) Network biology discovery: Multi-omic analysis This approach utilises individuals and defined com/content/dam/Deloitte/uk/ at the gene, protein and metabolite level. (sub)-population-based cohorts that have a com - Documents/-sciences- health-care/measuring-the- mon network of disease taxonomy. In addition, it return-from-pharmaceutical- ii) Identification of potential targets: The network requires an integrated molecular and clinical pro - innovation-2014.pdf. biology analysis should provide a prioritised list of file of both the individual as well as the sub-popu - 6 Cook, D et al. Lessons target genes and/or proteins. lation-based cohort. We have argued that precision Learned from the Fate of medicine uses a ‘1-in-N’ model (in contrast to the Astra-Zeneca’s Drug Pipeline: A Five Dimensional Network. iii) Functional validation: Utilisation of RNAi ‘N-of-1’ personalised medicine model) 18 . This is Nature Reviews: Drug screens to either overexpress or knock down each of predicated on widely-used biostatistical data anal - Discovery. 13, 419-431 (2014). the selected genes in the system under investigation. ysis and ‘big data’ analytical tools, and forms the 7 DiMasi, JA, Grabowski, HG basis of precision medicine drug development 2. and Hansen, RW. Innovations iv) Drug candidate screen: Selected, prioritised in the Pharmaceutical Industry: New Estimates of R&D Costs. molecular targets that are expressed in the tissue or Precision medicine drugs J. Health Econ. 47, 20-33, organ under investigation. Precision medicine drugs are defined as “those (2016). therapeutic products for which the label includes 8 Gaffney, A. How Often Does v) Target selection evaluation: Any target must be reference to specific biological marker(s), identi - FDA Withdraw Drugs Using expressed in the pathobiological tissue or organ fied by diagnostic tools, that help guide decisions Discontinuation Petitions? Very Rarely. Regulatory Affairs and causal onset, progression and dynamic (tem - and/or procedures for their use in individual Professional Society. June 15th, 2 poral) elements must be demonstrated. patients” . It is important to note that the physi - (2015). cian utilises the biological biomarker(s) listed on Clearly, there is much to do before systems biol - the drug label in prescribing the precision ogy can adequately demonstrate its routine and medicine drug. Last year the Center for Drug practical usefulness in DDD, but the trends dis - Evaluation and Research (CDER) at the FDA cussed here, albeit briefly, provide encouragement approved a record high 59 new drugs. However, Continued on page 39

Drug Discovery World Winter 2018/19 37 Systems Pharmacology

Figure 2: Comparison of the classic v systems biology v systems pharmacology approach. a) Representation of the one drug-one target model. b) Representation of a systems biology perspective of therapeutic drug effects . c) Representation of the one drug-multi-target-pathway/network approach of systems pharmacology. Note that the figure was adapted and modified from the work of Mikel Elorriaga (https://www.slideshare.net/mikeltxopiteaelorria/advanced- systems-biology-methods-in-drug-discovery)

24 (40%) of them were classified as ‘molecularly both numerous beneficial and adverse effects on targeted’ representing a new annual record for the patient. A well-known example of such a drug precision medicine drugs approved 31 . This contin - is aspirin. The drug manifests effects in the treat - ues the trend from 2017 where of the 46 new ment of inflammation, pain, fever, assorted can - drugs approved 16 of them (~35%) were classified cers, stroke and cardiovascular disease, but is also as precision medicine drugs2. The use of precision associated with gastritis and bleeding. Aspirin was medicine drugs is another example being recently reported to have an estimated 23 different employed by the pharmaceutical sector to improve putative targets, possibly explaining the the quality of therapeutic drugs provided to indi - pleiotrophic properties of the drug 32 . A 21st-cen - vidual patients. These advances are predicated on tury example of another widely-used pleiotrophic the advent of precision medicine and its focus on drug(s) is the statin family members. In both cases the grouping and identification of sub-populations the one drug-one target model was used originally (1-in-N model). In turn, precision medicine was in the development of such therapies, without the conceptualised from our more refined and detailed insights of drug promiscuity. understanding of human pathobiology and patho - physiology brought about by the development of Definitions systems biology tools, technologies and insights 17- The growing body of evidence from drug promiscu - 19,24,27 . ity and systems biology studies indicated that the ‘magic bullet’, one drug-one target model was sim - Systems pharmacology plistic. In part, this is due to the compensatory The old model of ‘one drug-one target’ was devel - mechanisms and redundant functions present in oped on the assumption that specific drug treat - biological systems, facilitating a resilience to single- ments would be superior due to the absence of off- target drug perturbations. Currently, it is under - target side-effects. However, the promiscuity of stood that many drugs bind to multiple targets that drugs that bind to numerous targets is now a well- in turn participate in, and are associated with, mul - characterised phenomenon 20-22 . Recently it was tiple biological processes. This property is referred estimated that promiscuity rates varied from 6-28 to as drug polypharmacology 22 . The term was individual targets per therapeutic drug 21 ! It is applied originally to off-target adverse effects of the noteworthy that armed with hindsight, most drug. More recently, the definition has morphed to Blockbuster Drugs (one drug-one target) are reflect the exploitation of these characteristics in a pleiotrophic in nature. In other words the drug has more beneficial manner. Polypharmacology is now

38 Drug Discovery World Winter 2018/19 Systems Pharmacology

defined as the design or use of a drug to either: i) toxicity and side-effect issues as well as limited effi - Continued from page 37 simultaneously interact with multiple functionally- cacy. In the case of multi drug-multi-targets (ie related targets that act together, or ii) inhibit targets combination therapy) such an approach is 9 ProCon,Org Thirty-Five FDA-approved Prescription that differ functionally from the primary target of designed to elicit synergistic effects brought about Drugs Later Pulled from the the drug to produce additional advantageous effects by different mechanisms of action by more than a Market. http://prescription for the individual patient 22 . single drug. In this context, systems pharmacology drugs.procon.org/view.resourc Our understanding of human complexity delin - is a one drug-multi-target model combined with e.php?resourceID=005528. eated by system biology studies combined with pathway/network analysis that should significantly 10 Vizirianakis, IS (Ed). Handbook of Personalized recognition of drug promiscuity and polypharma - enhance efficacy and reduce safety/toxicity effects. Medicine: Advances in cology led to the advent of ‘systems pharmacolo - Anighoro et al have suggested that while there is Nanotechnology, Drug gy’. This latter approach requires a comprehensive “…highly significant therapeutic relevance of com - Delivery and Therapy. CRC molecular/cellular profile of the healthy individu - bination therapies, [there are] potential advantages Press/Taylor Francis Group. al/population (systems biological profile), the dis - of a targeted therapy based on a single drug that Boca Raton, FL, USA. (2013). 11 Spear, BB, Heath-Chiazzi, M eased individual/population (systems pathobiolog - modulates the activity of multiple targets over sin - and Huff, JJ. Clinical 33 ical profile) and the corresponding response of the gle-targeted or combination therapy” . Some of Applications of individual/population to a drug (systems pharma - the advantages of systems pharmacology drugs Pharmacogenetics. Trends Mol. cological profile). The resultant comparative over combination therapies include: Medicine 7, 201-204 (2001). datasets from systems biology versus systems 12 Naylor, S. NostraPharmus Revisited: Splendid Isolation or pathobiology analyses and the corresponding drug i A single systems pharmacology drug with multi- Multifactorial Participation for effects profile constitutes a systems pharmacology target activity may have a more predictable, there - the Pharmaceutical Industry? approach. In addition the differences between fore superior pharmacokinetic (PK) profile com - Drug Discov. World. Summer these various states of the patient/population are pared to a number of individual drugs adminis - Supplement. 10-12 (2010). referred to as ‘systems response profiles’ 23 . A tered in combination. 13 Naylor, S. Technology: Bane or Bonanza for the schematic representation is captured in Figure 1 . ii Acute toxicity may be enhanced in more non- Pharmaceutical Industry. Drug As can be seen the fundamental principles for the selective combination therapies. Discov. World. Fall Edition. 51- one-drug-one target model are essentially the same iii Adverse synergistic effects may be more pro - 57 (2007). as a systems pharmacology approach. However at nounced in combination therapies. 14 Davidov, EJ, Holland, J, the systems level a multitude of targets, biomarkers iv The probability of developing target-based resis - Marple, E and Naylor, S. Advancing Drug Discovery and diagnostic components are all considered. The tance to multi-target drugs is statistically lower through Systems Biology. Drug resultant effect is a more comprehensively-defined than is the probability of developing resistance Discovery Today, 8, 175-181 health/disease/adverse framework of the individual against single-target drugs. (2003). /population as well as a safer, more efficacious v The administration of a single systems pharma - 15 Naylor, S. Systems Biology, drug. cology drug results in a more consistent and pre - Information, Disease and Drug Discovery. Drug Discov. World. Systems pharmacology is predicated on the dictable ADME profile. Winter Edition. 23-31 polypharmacology of therapeutic drugs. So what is vi Drug-drug interactions do not exist in a systems (2004/2005). the difference between the two terms? They are pharmacology regime. 16 Culbertson, AW, Valentine, both used as descriptors to describe efforts to over - vii A single agent binding to multiple targets might SJ and Naylor, S. Personalized come the one drug-one target model. Polypharma- be easier to develop given that the regulatory Medicine: Technological Innovation and Patient cology refers to a one drug-multi-target concept as requirements showing safety/efficacy of a drug Empowerment or Exuberant 1 utilised in drug repurposing . However, systems combination. Hyperbole? Drug Discov. pharmacology refers to a broader concept best cap - World. Summer Edition 18-28 tured as one drug-multi targets associated with For all these reasons, the development of single (2007). pathways and networks. Thus systems pharmacol - drugs with a desired multi-target profile defined 17 Naylor, S and Chen, SY. Unraveling Human Complexity ogy is based on the rational design of drug thera - by pathway/network analysis do offer a com - and Disease with Systems pies using information based on molecular, cellular pelling, cost-effective alternative to drug combi - Biology and Personalized and physiological complexity. This type of nations. Historically, drug combination therapy Medicine. Personal. Med. 7. approach produces systems pharmacology drugs has been more extensively explored in the clinic 275-287 (2010). rooted in molecular interactions between a single than the use of single multi-target drugs. 18 Naylor, S. What’s in a Name? The Evolution of “P- drug and multi-targets present in defined path - However, both approaches are likely to yield sin - Medicine”. J. Precision Med. 2, ways/networks. gle drugs or drug combinations with improved 15-29 (2015). safety and efficacy profiles. In either case, key to Combination therapy versus systems success will likely be the informed selection of pharmacology drugs suitable biological targets and molecular path - We have discussed above the limitations of the one ways/networks that need to be modulated with drug-one target compound that includes safety/ drug (s) 33 . Continued on page 41

Drug Discovery World Winter 2018/19 39 Systems Pharmacology

Table 2: Select examples of FDA-approved commercially-available systems pharmacology drugs

DISEASE SYSTEMS MULTI-TARGETS REFS INDICATION PHARMACOLOGY DRUG

CNS-Neurological

Schizophrenia, Adjuvent- Brexpiprazole (Rexulti) D2, 3 : 5H-T 1A , 2A , 2B , 7 : Alpha 1A , 1B , 1D , 2C 35

Parkinson’s Disease Safinamde (Xadago) MAO-B, Dopamine-RI, Blocks Na +/Ca 2+ Channels 35

Bipolar Mania Cariprazine (Vraylar) D2C , 2S , 3, 5H-T 1A , 2A , 2B , 2C , 7 :Alpha 1A : H 1 : mACh 35

Acute Mania Asenapine (Saphris) D1-4 : 5H-T 1A , 1B , 2A-C , 5A , 6, 7 : Alpha 2A-C : H 1,2 34

Oncology

Thyroid Cancer Lenvatinib (Lenvima) VEGFR 1, 2, 3 Kinases 35

Breast Cancer- Her2(+) Neratinib (Nerlynx) Her2, EGFR Kinases 35

Breast Cancer Ribociclib (Kisqall) Cyclin D1 : CDK 4, 6 35

AML- FLT3(+) Midostaurin (Rydapt) FLT3-mut : c-kit : PDGFR : src : VEGFR 35

Cardiovascular

Cardiac Arrhythmia Dronedarone (Mutaq) Na + & K +, L-type Ca 2+ channels 37

Infection

Hepatitis B, Adjuvent-HIV Tenofovir (Viread) Viral Reverse Transcriptase, DNA and Mitochondrial 38 DNA Polymerase

Implementation of systems pharmacology hensive understanding of target-disease associa - Talevi has discussed systems pharmacology drugs tions, pathway-target-drug-disease relationships, in the context of the substrate- ‘lock and as well as adverse events profiling capability. In key’ model. He has suggested that a multi-target addition it should be understood that target selec - drug could be conceived as a “skeleton or master tion is either additive (targets on the same path - key capable of [simultaneously] unlocking several way) or synergistic (targets on functionally com - locks”. However, he opined subsequently that such plementary pathways) in nature. a model was simplistic and did not adequately describe the effect of a drug on multi-targets over a ii) Drug candidate design/selection: The typical prolonged period of time due to significant up-and- approach is to integrate a different combination of down regulation of gene signatures 34 . A detailed pharmacophores (a molecular recognition feature comparative (ie the systems of a substrate/ligand necessary to bind to a biolog - response profile consisting of healthy versus patho - ical such as a target protein) into biological versus drug effect systems biology anal - the systems pharmacology drug candidate. The yses) is required to produce systems pharmacologic design of the candidate drug is typically defined by drugs 23 , but how to efficiently go about both ratio - the nature of the targets, the availability of starting nale target selection and drug candidate design in frameworks and the chemical tractability. Beyond such a ? Recently, Ramsey and col - that, the essential requirement of multi-target com - leagues discussed these issues and made the follow - pounds is that each pharmacophore retains the ing salient points presented below 35 : ability to interact with its specific target. These challenging tasks involve consideration of i) Target selection: It is necessary to have a compre - structure-activity relationships that determine

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substrate-target interactions. In addition, estab - and colleagues used this principle to guide the Continued from page 39 lishing the same degree of affinity for each target design of systems pharmacology drugs 22 . In their and minimising off-target, adverse effects are crit - study they associated multi-target drugs with 19 Waring, SC and Naylor, S. The Silent Epidemic of ical factors to be addressed. Ramsey has argued CATH functional families. (CATH is a of Alzheimer’s Disease: Can that “...the rational design of multi-target com - 95 million protein domains classified into 6119 Precision Medicine Provide pounds is far from being an easy task, dealing super families). They concluded that a small frac - Effective Drug Therapies? J. with the crucial issues of selecting the right target tion of a specific functional family of proteins Precision Med. 4. 38-49 (2016). combination, achieving a balanced activity (CATH-FunFams) were druggable and showed 20 Haupt VJ, Daminelli S and Schroeder, M. Drug towards them and excluding activity at the unde - using structural analyses that the domains in these Promiscuity in PDB: Protein sired target(s), while at the same time retaining families have the potential to be the druggable enti - Binding Site Similarity Is Key. drug-like properties” 35 . In order to achieve such a ties within drug targets 22 . PLoS ONE 8, (2013). difficult task a variety of approaches have been In the second example Thiel and co-workers out - http://www.plosone.org/article/ employed and include 22,33-35 : lined a detailed quantitative systems pharmacology info%3Adoi%2F10.1371%2Fjou rnal.pone.0065894. (QSP) approach to determine systems pharmacolo - 21 Hu, Y and Bajorath, J. i) Computational ligand discovery: A variety of gy drug properties through “a mechanistic consid - Monitoring Drug Promiscuity tools are used including chemoinformatics, virtual eration of processes underlying drug absorption, Over Time. F1000Research 3, screening, pharmacophore development, molecular distribution, metabolism and excretion (ADME) as (2014), Last updated: 25 docking and dynamics studies. well as the resulting drug action itself”, as well as November 2018. https://f1000 research.com/articles/3-218/v2. “a detailed description of drug pharmacokinetics 22 Moya-Garcia, A et al. ii) Quantitative Structure Activity Relationships (PK) and, simultaneously, drug pharmacodynamics Structural and Functional View (QSAR): Used in lead optimisation to correlate (PD)” 36 . In this study, a QSP approach was applied of Polypharmacology. Nature- molecular structure with pharmacological and bio - to quantify the drug efficacy of cyclooxygenase-2 Scientific Reports. 7, Article logical activity. (COX-2) and 5-lipoxygenase (5-LOX) inhibitors by Number 10102 (2017). https://www.nature.com/article coupling physiologically-based PK models, at the s/s41598-017-10012-x. iii) Biological validation of leads: Use of high whole-body level, with affected biological networks 23 van der Greef, J and throughput compound assessment and identifica - at the cellular scale. They presented results that McBurney, RN. Innovation: tion of pharmacophores. revealed insights about drug-induced modulation of Rescuing Drug discovery: In cellular networks in a whole-body context, thereby Vivo and Systems Pharmacology. Nature Rev. iv) Receptor biology and binding affinities: describing complex pharmacokinetic/pharmacody - Drug Discov. 4, 961-967 Screening compounds against specific targets. namic behaviour of COX-2 and 5-LOX inhibitors (2005). in therapeutic situations. The results demonstrated 24 Clish, C et al. Integrative v) Cell-based assays: Used as a preliminary screen - the clinical benefit of using QSP to predict drug effi - Biological Analysis of the ing tool. cacy and, hence, its value in helping to design opti - APOE*-Leiden Transgenic Mouse. . 8, 3-13 (2004). mal systems pharmacology drugs 36 . 25 See as an example: Yan, Q A number of the tools and technologies used in (Editor), Systems Biology in conventional DDD are also used in systems phar - Systems pharmacology drugs Drug Discovery and macology drug discovery. However, the advent of The concept of systems pharmacology drugs was Development: Methods and the systems biology toolbox facilitated the con - first suggested in 2000. In the intervening years the Protocols. In Methods in (Volume struction of pathways/networks to afford the one academic and pharmaceutical communities have 662). Humana Press (2016). drug-multi-target-pathway/network paradigm nec - enthusiastically developed this paradigm and now 26 Zou, J, Zheng, M-W, Gen, Li essary for the creation of systems pharmacology a significant number of such drugs are available on and Su, Z-G. Advanced drugs. the market today. Lin and colleagues noted that Systems Biology Methods in from 2000-15 the FDA approved a total of 361 Drug Discovery and Translational . Systems pharmacology approaches New Molecular Entity (NME) drugs. They esti - Biomed. Res. Intl. Article ID Two different brief descriptions of specific target mated that ~43% of those approved drugs had two 742835, (2013). http://dx.doi. selection and drug candidate design/selection or more targets, although to be clear such entities org/10.1155/2013/742835. examples will serve to highlight the approaches were not necessarily designed as systems pharma - 27 Yensen, J and Naylor, S. The used in the implementation of systems pharmacol - cology drugs 37 . Subsequently, Ramsey and col - Complementary Iceberg Tips of Diabetes and Precision ogy. In the former case the identification of individ - leagues did a similar study (2015-17) and noted Medicine. J. Precision Med. 3, ual targets and synergistic combinations of targets that of the 101 NME drugs approved by the FDA, 39-57 (2016). is critical to the systems pharmacology discovery 34% were single target drugs, 21% were multi-tar - process. Most target proteins consist of more than get drugs and 10% were combination therapies. one structural domain, but there is a “limited They concluded that these numbers “...unequivo - repertoire of domain types”. Since protein domains cally supports the attractiveness...” of systems mediate drug-protein interactions, Moya-Garcia pharmacology drug strategies 35 . Continued on page 42

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Continued from page 41 The systems pharmacology drugs approved by DRPx approach. Talevi has argued that in contrast the FDA between 2015-17 were predominantly prospective DRPx should explore drug-reposition - 28 Bennett, DA. Yu, L and De anti-neoplastic agents constituting 12 of the 21 ing possibilities much earlier in the drug discovery Jager, PL. Building a Pipeline to (57%) approved NMEs. An additional four process. This would entail the design of multi-pur - Discover and Validate Novel Therapeutic Targets and Lead approved systems pharmacology drugs were thera - pose drugs to treat different indications; such as Compounds for Alzheimer’s pies for CNS indications, with the remaining five co-morbidity disorders (eg diabetes and cardiac Disease. Biochem. Pharmacol. drugs approved for anti-infective, musculoskeletal, disease). 88, 617-630 (2014). genitourinary and alimentary tract /metabolism 29 Christensen, CM, disorders 35 . Systems pharmacology drugs are most Grossman, MD and& Hwang, J. Conclusions The Innovator’s Prescription: A relevant for disease states involving large target The reality of the one drug-multi-target- Disruptive Solution for Health networks and pathways, as is the case with most pathway/network systems pharmacology drug Care. McGraw-Hill, New York, cancers. Cancer cells are characterised by a trans - appears to afford considerable advantages over the NY, USA. (2009). formed associated with uncontrolled one drug-one target or combination drug-multi tar - 30 US National Research proliferation and immortality. This abnormal cell get approaches. However, the tremendous thera - Council. Toward Precision Medicine: Building a activity is sustained by significant protein deregu - peutic potential of multi-target drugs, their ratio - Knowledge Network for lation. For example, the protein kinase family con - nal discovery and their development still represent Biomedical Research and a sists of more than 500 different proteins and they a formidable challenge. In addition the necessity of New Taxonomy of Disease. US are involved in multiple cellular pathways and net - balancing the beneficial polypharmacology versus National Academies Press, works. The original one drug-one target model the harmful promiscuity of such drugs still needs to Washington DC USA (2011). http://www.nap.edu/catalog/13 produced highly-selective kinase inhibitors. be evaluated as more of these drugs are brought to 284/toward-precision- However, it has become increasingly clear that market. Nonetheless, building on the accumulated medicine-building-a- more effective targeted therapies based on kinase evidence, the concept of systems pharmacology knowledge-network-for- inhibitors should target the disease at multiple tar - drugs has made rapid and spectacular progress biomedical-research. get nodes in the network, which explains the sig - from being an emerging paradigm when first enun - 31 GenomeWeb. 2018: More Drugs, nificant efforts to create systems pharmacology- ciated at the beginning of 2000 to one of the Greater NGS Adoption, based kinase inhibitors in the treatment of several hottest topics in drug discovery and development Growing Appreciation of Dx forms of cancer. A representative sample of FDA in 2017-18. Does the merging of systems biology, Value. December 26th, 2018. approved marketed systems pharmacology drugs precision medicine, precision medicine drugs and https://www.genomeweb.com/ in oncology are shown in Table 2 . now systems pharmacology drugs provide the molecular- diagnostics/personalized- We concur with Talevi that there are three more harbinger of more safe and efficacious drugs? medicine-2018-more-drugs- general applications where systems pharmacology Initial indications appear to suggest that there is greater-ngs-adoption- drugs can be expected to impact in the future. indeed a new dawn breaking for patients and the growing#.XC1VA_x7nEY. Firstly, and as noted above, complex disease condi - products they rely on to keep them healthy and 32 Dai, S-X et al. Proteome- tions such as cancer and CNS disease are a clear alive. DDW Wide Prediction of Targets for Aspirin: New Insight into the focus of current effort and development ( Table 2 ). Molecular of Another area of applicability is in drug resistance. Aspirin. PeerJ 4:e1791 (2016). The ability to simultaneously modulate different Dr Kirkwood A. Pritchard Jr is a Co-Founder, https://doi.org/10.7717/ targets could be advantageous to individuals CSO and Board Director of ReNeuroGen LLC, a peerj.1791. expressing intrinsic or induced variability in drug virtual pharmaceutical company developing sys - 33 Anighoro, A, Bajorath, J and Rastelli, G. Polypharmacology: response due to modifications in key disease-rele - tems pharmacology therapies for the treatment of Challenges and Opportunities vant biological pathways and activation of com - neurological diseases. He is also a Co-Founder and in Drug Discovery. J. Med. pensatory mechanisms 34 . Apart from the obvious Board Director of HDL-Dx, a diagnostics compa - Chem. 57, 7874-7887 (2014). applications in the field of antimicrobial ny developing an assay to determine functionality 34 Talevi, A. Multiple-Target chemotherapy (it is less probable to develop resis - of HDL. In addition, he is a tenured Research Pharmacology: Possibilities and Limitations of the “Skeleton tance linked to single-point against Professor in the Division of Pediatric Surgery, Key Approach” from a multi-target than single-target agents) this strategy Department of Surgery, at the Medical College of Medicinal Chemist Perspective. could also be pertinent to treat non-infectious con - Wisconsin (Milwaukee, Wisconsin, USA). He has Front. Pharmacol. 22nd ditions characterised by high incidence of the drug broad and diverse interests September (2015). https://doi. resistance phenomena, eg epilepsy. One final appli - in a number of disease indications including stroke, org/10.3389/fphar.2015.00205. cation for consideration is in prospective Drug multiple sclerosis, traumatic brain injury, sickle cell Repositioning. We have previously highlighted the disease and bronchopulmonary dysplasia in pre - resurgence of Drug Repurposing and mature babies. He holds a PhD from Ohio State Repositioning (DRPx) 1. However, most such cases University (Columbus, Ohio, USA) and undertook have occurred by serendipity or exploitation of the a postdoctoral fellowship at Albert Einstein Continued on page 43 original mechanism of action, using a retrospective College of Medicine (New York, NY, USA).

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Dr Dustin P. Martin is a research scientist at the Continued from page 42 Medical College of Wisconsin (Milwaukee, Wisconsin, USA). He has served as an Adjunct 35 Ramsey, RR et al. A Perspective on Multi-Target Professor of Biology at both St Mary’s University Drug Discovery and Design and Winona State University (both in Winona, for Complex Diseases. Clin. Minnesota, USA). His current research interests Transl. Med. 7, (2018) doi: include systems pharmacology predicated on pep - 10.1186/s40169-017-0181-2. tide-based anti-inflammatory peptides in a number 36 Thiel, C et al. Using Quantitative Systems of neutrophil-mediated diseases such as stroke, Pharmacology to Evaluate the traumatic brain injury, sickle cell disease and bron - Drug Efficacy of COX-2 and 5- chopulmonary dysplasia. In addition he has LOX Inhibitors in Therapeutic research and entrepreneurial interests in neurode - Situations. Using Quantitative generative diseases such as prion-mediated diseases Systems Pharmacology to Evaluate the Drug Efficacy of and Alzheimer’s Disease. He received his PhD in COX-2 and 5-LOX Inhibitors and Molecular, Cellular and in Therapeutic Situations. from Iowa State Systems Biol. Appl. Article University. Number 28 (2018). doi.org/10.1038/s41540-018- 0062-3. Dr Stephen Naylor is a Co-Founder, CEO and 37 Lin, H-H, Zhang, L-L, Yan, R Board Chairman of ReNeuroGen LLC, a virtual et al. Network Analysis of pharmaceutical company developing systems phar - Drug–Target Interactions: A macology therapies for the treatment of neurologi - Study on FDA-Approved New cal diseases. He is also a Co-Founder, COO and Molecular Entities Between 2000 to 2015. Science Board Chairman of iMetabolic Biopharma Reports.7, Article Number Corporation. In addition he is the Founder, 12230, (2017). doi: Chairman and CEO of MaiHealth Inc, a 10.1038/s41598-017-12061-8. systems/network biology level diagnostics compa - 38 De Castro, S and ny in the health/wellness and precision medicine Camarasa, M-J. Can a Drug with Simultaneous Action sector. He was also the Founder, CEO and Against Two Relevant Targets Chairman of Predictive Physiology & Medicine be an Alternative to (PPM) Inc, one of the world’s first personalised Combination Therapy? Eur. J. medicine companies. He serves also as an Advisory Med Chem. 150, 206-227 Board Member of CureHunter Inc, a computation - (2018). al biology drug discovery company, and as a busi - ness adviser to the not-for-profit Cures Within Reach. In the past he has held professorial chairs in & Molecular Biology; Pharmacol- ogy; Clinical Pharmacology and Biomedical , all at Mayo Clinic in Rochester, MN, USA. He holds a PhD from the University of Cambridge (UK), and undertook a NIH-funded fellowship at MIT located in the ‘other’ Cambridge, USA. Address correspondence to him at [email protected].

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