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Chapter 11. the Drug Discovery Process

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Chapter 11. the Drug Discovery Process Chapter 11 The Drug Discovery Process Success is the ability to go from failure to failure with no lack of enthusiasm... — Winston Churchill (1874À1965) I am interested in physical medicine because my father was. I am interested in medical research because I believe in it. I am interested in arthritis because I have it... — Bernard Baruch, 1959 ...new techniques may be generating bigger haystacks as opposed to more needles ... — D.F. Horrobin, 2000 11.1 Some Challenges for Modern Drug 11.5 Types of Therapeutically Active 11.8 Pharmacodynamics and High- Discovery Ligands: Polypharmacology Throughput Screening 11.2 Target-Based Drug Discovery 11.6 Pharmacology in Drug Discovery 11.9 Drug Development 11.3 Systems-Based Drug Discovery 11.7 Chemical Sources for Potential 11.10 Clinical Testing 11.4 In vivo Systems, Biomarkers, and Drugs 11.11 Summary and Conclusions Clinical Feedback References 11.1 SOME CHALLENGES FOR MODERN robotic screening using simplistic single gene target DRUG DISCOVERY approaches (inappropriate reliance on the genome as an instruction booklet for new drugs) coupled with a de- The identification of primary biological activity at the tar- emphasis of pharmacological training may have combined get of interest is just one of a series of requirements for a to cause the current deficit in new drugs [2]. The lack of drug. The capability to screen massive numbers of com- success in drug discovery is reflected in the number of ELSEVIERÀ drugs that have failed in the transition from Phase II clini- pounds has increased dramatically over the past 10 15 years, yet no corresponding increase in successfully cal trials (trial in a small number of patients designed to launched drugs has ensued. As discussed in Chapter 9, determine efficacy and acute side effects) to Phase III there are required pharmacokinetic properties and absence clinical trials (larger trials meant to predict effects in of toxic effects that must be features of a therapeutic overall populations and determine overall risk-to-benefit entity. As more attention was paid to absorption, distribu- ratio of a drug); see Figure 11.2. While 62 to 66% of new tion, metabolism, and excretion (ADME) properties of drugs entering Phase I passed from Phase II to Phase III chemical screening libraries, toxicity, lack of therapeutic in the years 1995 to 1997, this percentage fell to 45% in efficacy, and differentiation from currently marketed 2001À2002 [3]. In view of the constantly increasing num- drugs have become the major problems. As shown in ber of new drugs offered for clinical trial, this suggests Figure 11.1, the number of new drug entities over the that the quality of molecules presented to the clinic is years has decreased. This particular representation is nor- diminishing compared to that seen 10 years ago. malized against the increasing costs of drug discovery At the heart of the strategies for drug discoveries are and development, but it does reflect some debilitating two fundamentally different approaches; one focusing on trends in the drug discovery process. Undue reliance on the target, in which a molecule is found to interact with a T. P. Kenakin: A Pharmacology Primer, Fourth edition. DOI: http://dx.doi.org/10.1016/B978-0-12-407663-1.00011-9 © 2014 Elsevier Inc. All rights reserved. 281 282 Chapter | 11 The Drug Discovery Process 120 Reductionist systems most often are recombinant ones with the target of interest (for example, human G protein 100 coupled receptor [GPCR] expressed in a surrogate cell). The 80 nature of the cell is thought to be immaterial, since the cell 60 is simply a unit reporting activation of the target of interest. For example, belief that peptic ulcer healing is facilitated by 40 blockade of histamine H2 receptor-induced acid secretion 20 suggests a reductionist system involving antagonism of his- NCE output per dollar (normalized to 1970–1975) tamine response in surrogate cells transfected with human 0 1975 1980 1985 1990 1995 2000 histamine H2 receptors. In this case, refining primary activ- Year ending five-year frame ity when the target-based activity disease relationship has FIGURE 11.1 Histograms show the number of new drugs (normalized been verified is a useful strategy. It can also be argued that for the cost of drug discovery and development in the years they were considerable value may be mined in this approach, since developed) as a function of the years they were discovered and devel- “first in class” often is not “best in class.” oped. Adapted from [1]. Focusing in on a single target may be a way of treat- ing a disease, but not necessarily of curing it. The inter- play of multiple genes and the environment leads to 800 # new drugs entering phase I complex diseases such as diabetes mellitus, coronary # drugs from phase II to phase III 700 artery disease, rheumatoid arthritis, and asthma. To con- 600 sider this latter disease, it is known that bronchial asthma 500 is the result of airway hyper-reactivity that itself is the 400 result of multiple system breakdowns involving allergic sensitization, failure of neuronal and hormonal balance to 300 airway smooth muscle, and hyper-reactivity of smooth 200 muscle. Bronchial spasm can be overcome by a system 100 override such as powerful β-adrenergic muscle relaxation, 0 providing a life-saving treatment, but this does not 1995 1996 1997 1998 1999 2000 2001 2002 address the origins of the disease, nor does it cure it. The FIGURE 11.2 Histograms showing the number of new drug entities divergence in Phase II from Phase III studies shown in entering Phase I clinical development (blue bars) and, concomitantly, Figure 11.2 is cited as evidence that the target approach the number entering Phase III development, as a function of year. Adapted from [2]. is yielding molecules, but that they may be the wrong molecules for curing (or even treating) the disease. single biological target thought to be pivotal to the dis- Whereas in physics, the path from the fundamental par- ease process, and one focusing on the complete system. It ticle to the complex matter is relatively linear (reduction- is worth considering these separately. ism requires linearity and additivity), in biology it often is extremely nonlinear. This can be because of system- specific modifications of genes and highly complex inter- 11.2 TARGET-BASED DRUG DISCOVERY actions at the level of the cell integration of the genes. ELSEVIERThis can lead to some impressive disconnections; for A target-based strategy for drug discovery has also been example, the principal defect in type I diabetes is well referred to as a reductionist approach. The term origi- known but targeted approaches have still been unable to nates in physics, where it describes complex matter at the cure the disease. In theory, pathways can be identified in level of fundamental particles. In drug discovery, target- disease processes, critical molecules in those pathways based refers to the fact that the responsible entity for a identified, prediction of the effects of interference with the pathological process or disease is thought to be a single function of those molecules determined, and the effect of gene product (or small group of defined gene products) this process on the disease process observed. However, and is based on the premise that isolation of that gene this simple progression can be negated if many such path- product in a system is the most efficient and least ambig- ways interact in a nonlinear manner during the course of uous method of determining an active molecule for the the disease. In fact, in some cases the design of a surrogate target. Reductionist approaches are best suited for “me system based on the target may be counterproductive. For too” molecules with well-validated targets when the first example, for anticancer drugs, the test system tumors are in class already exists. They also are well suited to sometimes chosen or genetically manipulated for sensitiv- Mendelian diseases such as cystic fibrosis and sickle cell ity to drugs. This can make the models overpredictive of anemia, where the inheritance of a single gene mutation drug activity in wild-type tumors where multiple pathways can be linked to the disease. may be affected by numerous accumulated mutations 11.2 TARGET-BASED DRUG DISCOVERY 283 FIGURE 11.3 Venn diagram indicating the human genome and the subsets of genes thought to mediate disease and those that are Human genome ≈ 30,000 genes druggable (thought to be capable of influence by small molecules, i.e., proteins). The inter- section of the subsets comprises the set that should be targeted by drug discovery. Adapted from [5]. Druggable Drug targets Disease-modifying genome ≈ 3000 ≈600–1500 genes ≈ 3000 and/or chromosomal abnormalities used to maintain their steps are common to all modes, that is, screening and phenotype. A classic example of where a single target fails lead optimization are required. However, the target vali- to emulate the properties of diseases is in the therapy of dation step is unique to target-based drug discovery. psychiatric disorders. These diseases have a shortage of Once a target-based approach is embarked upon, the validated targets (it is unlikely that there are single gene choice of target is the first step. In biological systems, lesions accounting for psychiatric disorders), and the high- there are generally four types of macromolecules that can throughput screening systems bear little resemblance to interact with druglike molecules: proteins, polysacchar- the in vivo pathology. Genetic approaches in psychiatry ides, lipids, and nucleic acids. As discussed in Chapter 1, are problematic since the effects of “nurture” and epige- by far the richest source of targets for drugs is proteins.
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