DRUDIS 1532 1–6 Drug Discovery Today Volume 00, Number 00 November 2014
PERSPECTIVE
feature Target selection for FDA-approved medicines Q1 Michael S. Kinch1, [email protected], [email protected], Denton Hoyer2, Eric Patridge2 and Mark Plummer2
Introduction Recent years have witnessed a revolution in the fundamental understanding of disease etiology. Such knowledge gave rise to targeted therapies meant to prevent or ameliorate disease selectively while minimizing damage to normal cells and tissues. The concept of rational drug design was initiated by a handful of pioneers, including Gertrude Elion, George Hitchings and James Black in the latter half of the 20th Century [1,2]. These investigators demonstrated that knowledge of the identity and function of particular targets can be implemented to design and test new medicines. This fostered a revolution in rational drug design to identify crucial molecular targets that can be perturbed (either increasing or decreasing function) to prevent or reverse disease and/or symptoms [3]. The present study sought to assess the mechanistic basis of all new molecular entities (NMEs) approved by the FDA, with emphasis on
relating targets to therapeutic application. To accomplish this goal, the targets for all NMEs, approved as of the end of 2013 (1453 in total), were compiled and assessed using current knowledge of the modes of action. The mechanism and targets for each NME were assessed by literature reviews of multiple sources, including publically available information provided to the FDA during the review process (http:// www.fda.gov/) as well as information from PubMed (National Center for Biotechnology Information, Bethesda, MD, USA), DrugBank (The Metabolomics Innovation Center, University of Alberta, Edmonton, Alberta, Canada), SciFinder (American Chemical Society, Washington, DC, USA) and other online resources. For each NME in which a target has been identified, the target family was also catalogued. All target families containing at least five NMEs are shown (Fig. 1). The identities of the ten most common target families account for more than
three-quarters (78%) of all FDA-approved NMEs. G-protein-coupled receptors (GPCRs) constituted the largest grouping of targets, capturing more than one-quarter of all NMEs. The most commonly targeted GPCRs included adrenoceptors (78 NMEs) and cholinergic receptors (61 NMEs). Membrane channels and transporters were the second largest target class (211 NMEs), followed by targets involved in nuclear signaling (107 NMEs), proteases (67 NMEs) and oxygenases (52 NMEs).
Prominent target families Following up on the general observations about families targeted by FDA-approved NMEs, certain families were examined in greater detail. Specifically, the mechanistic basis of drug action was related to clinical indications and questions were asked as to how target prosecution has changed over time. The three largest families (GPCR, channels and transporters, and nuclear
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1359-6446/06/$ - see front matter ß 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.drudis.2014.11.001
Features PERSPECTIVE
The biopharmaceutical industry translates fundamental understanding of disease into new medicines. As part of a comprehensive analysis of FDA-approved new molecular entities (NMEs), we assessed the mechanistic basis of drug efficacy, with emphasis on target selection. Three target families capture almost half of all NMEs and the leading ten families capture more than three-quarters of NME approvals. Target families were related to their clinical application and identify dynamic trends in targeting over time. These data suggest increasing attention toward novel target families, which presumably reflects increased understanding of disease etiology. We also suggest the need to balance the ongoing emphasis on target-based drug discovery with phenotypic approaches to drug discovery.
1
DRUDIS 1532 1–6 PERSPECTIVE
Drug Discovery Today Volume 00, Number 00 November 2014
(a)
Targetclass
NME
GPCR Adrenoceptor (78) Acetylcholinereceptor(61)
397
Channel Sodiumchannel(49) GABA(41)
147
Nuclearsignaling Glucocorticoidreceptor(37) Estrogenreceptor(17)
104
Protease Thrombin(14) Acetylcholine esterase(12)
66
Transporter Norepinephrine (15) Serotonin(15)
65
Transpeptidase Penicillin-bindingprotein(54)
54
Oxygenase Cyclooxygenase(28) Monoamineoxidase (8)
52
Polymerase DNApolymerase(20) RNA polymerase(17)
45
Kinase Tyrosinekinase (35) Serine/threonine kinase (4)
43
Cytokine Interferon (10) Interleukin(7)
37
(b) Targetclass
NME
Ribosome
34
Synthase
32
Isomerase
31
Alkylating agent
23
Sterol
20
Esterase
19
Reductase
19
Dehydrogenase
12
Enzyme replacement
11
Tubulin
10
Celladhesion
7
Anhydrase
6
Carboxylase
6
Chelator
6
Transferase
5
Amidase
5
Othertarget
102
Unclear mechanism
95
Features PERSPECTIVE
Drug Discovery Today
FIGURE 1
Target classes for FDA-approved new molecular entities. The targets for all FDA-approved new molecular entities (NMEs) were identified and grouped into the 23 classes indicated. For the leading ten targets (a), the two most popular target subfamilies were also identified, along with the number of NMEs targeting them (in parentheses). (b) Additional prominent target families are shown, along with the number of NMEs targeting each.
receptors) were assessed first given their prominence, collectively encompassing almost half (47%) of all NMEs approved by the FDA. Each of the three largest families has persistently been targeted since the beginning of the modern drug discovery era (in the early 1950s) (Fig. 2a). At present, an average of almost five NMEs targeting GPCRs is approved each year. Likewise, almost two NMEs targeting channels and transporters and nuclear receptors are approved each year. The popularity of these three major target classes is reinforced by evidence that each has been applied to a broad array of therapeutic indications. The prominence of GPCR targets for cardiovascular indications largely reflects the role of adrenoceptor antagonists for the treatment of hypertension and beta adrenergic agonists and antagonists for cardiovascular Q2 function [5]. Herein we broaden the study to all major indications and show GPCR-modifiers dominate many other indications (Fig. 2b). 2
GPCRs are the targets for 28 of 105 (27%) of NMEs for neurological diseases, 35 of 80 (44%) NMEs approved for psychiatric indications and 46 of 63 (73%) NMEs for pain and anesthesia. The high frequency of GPCR targeting of these indications can be attributed to a handful of targets, including muscarinic acetylcholine receptor (for neurological indications), serotonin and dopamine (for psychiatric indications) and opioid receptors (for pain and anesthesia). GPCRs are underrepresented in terms of NMEs for infectious diseases, capturing five of 293 (2%) NMEs. A different subset of clinical indications were the targets of NMEs that modify ion channels (Fig. 2c) and nuclear receptors (Fig. 2d). Specifically, NMEs targeting ion channels were common for NMEs approved for pain and anesthesia (33 of 63; 52%), neurological (39 of 105; 37%) and sleeping (12 of 27; 44%) disorders. These findings include the development of local anesthetics that target sodium channels as well as
GABA agonists as sedatives [7,8]. Targeting of nuclear receptors tended to emphasize immunological (40 of 173; 23%) and hormone and reproductive (32 of 75; 43%) applications, reflecting the prominence of steroidal elements such as glucocorticoid as well as estrogen and progesterone receptors, respectively. Beyond evaluating the most common target classes, we sought to identify trends over time. Transpeptidases and isomerases were transiently popular (Fig. 3a). Transpeptidases and isomerases were most commonly utilized as targets for infectious diseases (Fig. 2b). All 58 transpeptidase-based NMEs target bacterial pathogens [9]. Their rise and decline reflects the emergence of beta-lactam-type antibiotics in the decades following 1960 and the abrupt decline in antibiotic research during recent years [10,11]. The popularity of other target families has also grown in recent years (Fig. 3c). As detailed previously, kinase-based targeting has come to dominate oncology [12]. This trend began in the
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Q3
DRUDIS 1532 1–6 Drug Discovery Today Volume 00, Number 00 November 2014
PERSPECTIVE
(a)
(b) 16
GPCR
GPCR
Annualapprovals
Channel 12
Ophthalmology 20
Nuclearreceptor
10
Other 89 Psychiatric 35
Oncology 16
8
Neurological 28
6 4
Pain& anesthesia 46
Immunological 60
2 0 1931
1941
1951
1961
1971
1981
1991
2001
Digestive 40
2011
Year
Ionchannelandtransporter
(c)
Other,9
Neurological, 27
Metabolic,10 Immunological,0 Digestive,0
Sleeping,12
Infectious,8 Pain& Anesthesia,32 Cardiovascular, 40
Nuclearreceptor
(d)
Psychiatric,9 Respiratory,0
Cardiovascular 63
Metabolic,5
Oncology, Other,9 11 Reproductive,9 Bone,5
Addiction,0
Cardiovascular,4 Immunological, 40
Hormonal,17
Features PERSPECTIVE
14
Drug Discovery Today
FIGURE 2
G-protein-coupled receptors (GPCRs), channels and nuclear receptors. (a) The average annual approval rates for new molecular entities (NMEs) targeting the indicated target families is shown on a decade-by-decade basis. The clinical indications for each NME are shown for (b) GPCRs, (c) ion channels and transporters and (d) nuclear receptors.
1980s and that 75% of kinase inhibitors target Q4 cancer (data not shown). Another distinguishing
feature of the current study is a demonstration that most kinase inhibitors (35 of 43; 81%) are directed at tyrosine kinases (Fig. 1a). Cytokine-based medicines also rose with the growth in kinase inhibitors, (Fig. 3c). The first recombinant interferon was approved in 1986 for treatment of viral infections [13]. Since that time, the use of cytokines has increased, in terms of the target families as well as the indications, including use for the treatment of bone maladies (seven of 27; 26%), immunological disorders (17 of 173; 10%), oncology (nine of 170; 5%) and infectious diseases (seven of 293; 2%) (Fig. 3d). The prominence of cytokine targeting peaked at two NMEs per year in the first decade of the new millennium and has decreased in recent years. It is too early to determine whether this suggests that targeting of cytokines, like that of isomerases and transpeptidases, has peaked and is now declining.
Protease-based targeting has also grown in popularity in recent years [14]. At present, an average of four NMEs targeting proteases is approved each year (Fig. 3c). Protease targeting has grown dramatically since the 1990s. The initial wave of protease approvals largely reflects the success of modifiers of angiotensin-converting enzyme, a protease regulating blood pressure [15]. Subsequent breakthroughs in molecular modeling and therapeutic challenges surrounding the HIV pandemic facilitated the development of a series of selective inhibitors of HIV (ten NMEs) [16] and later hepatitis C virus (HCV) proteases (three NMEs). Beyond viral applications, targeting of proteases is now shared among many therapeutic indications including additional cardiovascular and infectious diseases, as well as metabolic disorders and oncology (Fig. 3d). It is easy to forget that, for many medicines approved in the time period ranging from the 1930s through the 1980s, the fact that a protease
was being targeted was unknown or unexpected. In hindsight, we are able to establish these relationships. Thus, the mechanistic analyses of FDA-approved NMEs herein is based on current knowledge of drug activity and target function, often revealed well after a drug has reached the market. A widely held view is that regulatory approval for a new medicine requires fundamental understanding of drug activity and target function in diseased and normal cells. The rationale is to maximize efficacy and minimize toxicity by targeting pathways that are most relevant to the disease while avoiding those that could be important for normal (nondiseased) cell survival or function. One can argue this approach increases the efficacy and safety of new medicines, thereby reducing the likelihood of unanticipated side-effects (e.g. those encountered post-approval with thalidomide or rofecoxib). Indeed, the rational design of HIVprotease inhibitors provided a benchmark for establishing relatively safe and effective
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DRUDIS 1532 1–6 PERSPECTIVE
(a)
Drug Discovery Today Volume 00, Number 00 November 2014
(b)
5
Isomerase
Transpeptidase
Annual approvals
Transpeptidase 4
Isomerase
3 Oncology, 10 Infectious, 16
2 1
Immunological, 5 Infectious 54
0 1931 1941 1951 1961 1971 1981 1991 2001 2011
Year (c)
Cytokine
(d)
Protease
6
Protease Annual approval
5
Bone, 4
Cytokine
Other, 14
4
Oncology, 9 Infectious, 7
3
Metabolic, 5
Cardiovascular, 32
2 Immunological, 17
1
Infectious, 15
0 1931 1941 1951 1961 1971 1981 1991 2001 2011
Year Drug Discovery Today
Features PERSPECTIVE
FIGURE 3
Changing emphasis on target families over time. (a) The average annual approval rates for target families that (a) peaked in popularity and subsequently declined or (c) are undergoing growth is shown. (b,d) The therapeutic applications of these new molecular entities (NMEs) are indicated. Please note that the growth of kinase-based drugs for oncology is reviewed elsewhere [12].
therapeutic strategy [17]. Rational design assumes one has accurate knowledge of the most effective targets and can implement this to design ideal medicines [18] and could eliminate the serendipity often associated with phenotypic strategies that conveyed many successful medicines [19]. Indeed, a recent study emphasizes the success of phenotypic approaches as compared with target-based design [20]. The database of FDA-approved drugs was analyzed to assess those NMEs, where the mechanistic basis of efficacy remains unclear or controversial (Fig. 4a). The targets or mechanisms for 95 NMEs remain unclear (Fig. 1b). Viewed over time, the rate of approval for NMEs with an uncertain mechanism has remained stable (Fig. 4a) and has been applied to many different indications (Fig. 4b). This outcome was unexpected in light of the emphasis on rational design over the past few decades. One might have predicted that the fraction of approvals of drugs with unknown mechanism would decrease as our understanding of drug targets increases. 4
Whereas the work above contrasted wellestablished versus unknown targets, the final set of studies looked beyond the largest target families (Fig. 4c). All NMEs recognizing targets beyond the leading 20 families were collected and evaluated as a surrogate for novelty. When viewed over time, approval of NMEs recognizing these ‘other’ targets has increased steadily (Fig. 4c). In the 1950s only 1% of NMEs recognized targets outside the 23 families. This now represents 16% of NMEs approved in the current decade. Likewise, less conventional target families are broadly distributed among many indications (Fig. 4d). These are optimistic signs suggesting that increased understanding of disease is translating into novel therapeutics.
Concluding remarks The major finding of our present study is an assessment of the breadth of molecular targets recognized by FDA-approved therapeutics. Ten target families capture more than three-quarters of all NMEs. Three families alone (GPCRs, channels and transporters, and mediators of nuclear
signaling) account for almost one-half of all FDAapproved NMEs. The emphasis on target families has changed over time. Whereas the ‘big three’ families have consistently been the focus of new drug development, emphasis on other families has varied over time. Mechanisms unique to antibacterial agents rapidly peaked and declined and thus are reflective of overall declines in new antibiotic development [10,11]. Other target families, such as kinases and proteases, are in the midst of a renaissance. Both families are undergoing steady growth, in terms of the absolute number of approvals as well as their breadth of application to different disease types. Cytokine-based drugs could be arriving at a crucial inflection point. This family of targets grew in popularity from the 1980s through 2010. Data from recent years could indicate that cytokine-based drugs have peaked and are beginning to decline (similar to that observed with transpeptidases more than a decade ago), although it remains to be determined if this simply reflects an unrepresentative slow start in the current decade or whether such a trend persists.
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DRUDIS 1532 1–6 Drug Discovery Today Volume 00, Number 00 November 2014
(a)
PERSPECTIVE
(b)
Unclear mechanism
Oncology, 10
Annual approvals
7 6
Neurologic al, 12
5 4
Other, 8
Cardiovascular, 7
Immunological, 7
3 Dermatology, 5
2 1
Infectious, 29
0 1931
1941
1951
1961
1971
1981
1991
2001
2011
Year
(c)
(d)
Novel or other targets
Cardiovascular 19
9
Annual approvals
8
Other 64
7 6
Infectious 42
5 4
Ophthalmology 9
3 2
Oncology 60
1 0 1931
1941
1951
1961
1971
1981
1991
2001
Immunology 14 Metabolic 16 Neurology 10
2011
Year Drug Discovery Today
The dominance of the largest three target families is worthy of further consideration. Clearly, these molecules present tractable targets. Past successes with one target probably inspired additional interest in the same or related molecules, which has been described as ‘creating a herd mentality’ [21]. Given such successes, it could be that the chemical libraries that are utilized to screen new targets are influenced by, and perhaps biased toward, such targets [22,23]. This would seem a reasonable expectation because the human genome is thought to encode an estimated 400 GPCRs [24], 232 ion channels [25] and 817 transporters [26]. Thus, the yield of new medicines might just be beginning. Extending this logic, opportunities for future targeting of nuclear receptors might not be as sustainable. The human genome encodes for 48 nuclear receptors [27] and these are targeted by 107 different NMEs. Whereas incremental improvements in nuclear receptor targeting are undoubtedly possible (e.g. by improving affinity or selectivity), this family is probably closer to saturation. Thus, future growth might not remain at the level of one or
two new annual approvals, which has persisted each year since the early 1950s. Increasing emphasis on new target families suggests new knowledge of disease biology is translating into new medicines. Such results suggest sustainability of new, and hopefully orthogonal, medicines. It is worth repeating that our studies herein utilize current information about target families, which illuminates the mechanism of past NMEs. At the time of approval, the mechanistic basis of many NMEs was unknown or unclear. In this context, it is important to remember that successful medicines, many of which are still considered safe and effective today, were derived from such an approach. Although rational drug design has also proven effective [28], it will be important to identify a healthy balance between rational design of known targets versus those identified by phenotypic screens and other approaches, collectively known as forward pharmacology, where the mechanistic basis of efficacy and toxicity might not yet be clear. Such a balance could avoid potential problems resulting from inaccurate perceptions about the most
important pathways at any given time for particular indications. One might argue that phenotypic strategies can serve to identify novel targets and pathways and thereby favor subsequent generations of rationally designed drugs. Thus, the two approaches can work together hand-in-hand to ensure continued innovation.
Uncited references
Q5
[4,6].
Acknowledgments This work was conducted as part of a project at the Yale Center for Molecular Discovery (http:// ycmd.yale.edu/) to develop a collection of all FDA-approved small molecules as a resource for screening to emphasize drug repurposing. Please contact the authors if you or your organization would be interested in potential participation in this project. References 1 Elion, G.B. (1993) The quest for a cure. Ann. Rev. Pharmacol. Toxicol. 33, 1–23 2 Black, J. (1989) Drugs from emasculated hormones: the principle of syntopic antagonism. Science 245, 486–493
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Features PERSPECTIVE
FIGURE 4
Ambiguity and novelty in drug targeting. (a) The average annual approval rates for new molecular entities (NMEs) in which the mechanistic basis is unclear is shown on a decade-by-decade basis. (b) The clinical indications for each NME are indicated. (c) The approval rates and (d) therapeutic applications of NMEs recognizing novel target families (fewer than five representative NMEs) is indicated.
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3 Foye, W.O. et al. eds (2008) Foye’s Principles of Medicinal Chemistry, Lippincott Williams & Wilkins 4 Kinch, M.S. et al. (2014) An overview of FDA-approved new molecular entities: 1827–2013. Drug Discov. Today 19, 1033–1039 5 Cruickshank, J.M. (2010) Beta blockers in hypertension. Lancet 376, 415 author reply 415–416. 6 Kinch, M.S. et al. (2014) Trends in pharmaceutical targeting of clinical indications: 1930–2013. Drug Discov. Today doi: 10.1016/j.drudis.2014.05.021 7 Reves, J.G. et al. (1982) Calcium entry blockers: uses and implications for anesthesiologists. Anesthesiology 57, 504–518 8 Haefely, W. et al. (1975) Possible involvement of GABA in the central actions of benzodiazepines. Adv. Biochem. Psychopharmacol. 14, 131–151 9 Pestka, S. (1976) Insights into protein biosynthesis and ribosome function through inhibitors. Prog. Nucleic Acid Res. Mol. Biol. 17, 217–245 10 Kinch, M.S. et al. (2014) An analysis of FDA-approved drugs for infectious disease: antibacterial agents. Drug Discov. Today 19, 1283–1287 11 Outterson, K. et al. (2013) Approval and withdrawal of new antibiotics and other antiinfectives in the US, 1980–2009. J. Law Med. Ethics 41, 688–696 12 Kinch, M.S. (2014) An analysis of FDA-approved drugs for oncology. Drug Discov. Today doi: 10.1016/ j.drudis.2014.08.007
Drug Discovery Today Volume 00, Number 00 November 2014
13 Baron, E. and Narula, S. (1990) From cloning to a commercial realization: human alpha interferon. Crit. Rev. Biotechnol. 10, 179–190 14 Hooper, N.M., ed. (2002) Proteases in Biology and Medicine, Portland Press 15 Barger, A.C. (1976) Converting enzyme inhibition and blood pressure regulation. Agents Actions 6, 538–542 16 Meek, T.D. and Dreyer, G.B. (1990) HIV-1 protease as a potential target for anti-AIDS therapy. Ann. N. Y. Acad. Sci. 616, 41–53 17 Seelmeier, S. et al. (1988) Human immunodeficiency virus has an aspartic-type protease that can be inhibited by pepstatin A. Proc. Natl. Acad. Sci. U. S. A. 85, 6612–6616 18 Johnson, K.A. and Brown, P.H. (2010) Drug development for cancer chemoprevention: focus on molecular targets. Semin. Oncol. 37, 345–358 19 Lee, J.A. and Berg, E.L. (2013) Neoclassic drug discovery: the case for lead generation using phenotypic and functional approaches. J. Biomol. Screen. 18, 1143–1155 20 Swinney, D.C. (2013) Phenotypic vs. target-based drug discovery for first-in-class medicines. Clin. Pharmacol. Ther. 93, 299–301 21 Zanders, E.D., ed. (2011) The Science and Business of Drug Discovery: Demystifying the Jargon, Springer 22 Akella, L.B. and DeCaprio, D. (2010) Cheminformatics approaches to analyze diversity in compound screening libraries. Curr. Opin. Chem. Biol. 14, 325–330
23 Hert, J. et al. (2009) Quantifying biogenic bias in screening libraries. Nat. Chem. Biol. 5, 479–483 24 Bjarnadottir, T.K. et al. (2006) Comprehensive repertoire and phylogenetic analysis of the G proteincoupled receptors in human and mouse. Genomics 88, 263–273 25 Jegla, T.J. et al. (2009) Evolution of the human ion channel set. Comb. Chem. High Throughput Screen. 12, 2–23 26 Alme´n, M.S. et al. (2009) Mapping the human membrane proteome: a majority of the human membrane proteins can be classified according to function and evolutionary origin. BMC Biol. 7, 50 27 Robinson-Rechavi, M. et al. (2001) How many nuclear hormone receptors are there in the human genome? Trends Genet. 17, 554–556 28 Mavromoustakos, T. et al. (2011) Strategies in the rational drug design. Curr. Med. Chem. 18, 2517–2530
Michael S. Kinch1, Denton Hoyer2, Eric Patridge2, Mark Plummer2 1 Washington University in St Louis, St Louis, MO, USA 2 Yale Center for Molecular Discovery, West Haven, CT, USA
Features PERSPECTIVE 6
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PERSPECTIVE
feature Target selection for FDA-approved medicines Q1 Michael S. Kinch1, [email protected], [email protected], Denton Hoyer2, Eric Patridge2 and Mark Plummer2
Introduction Recent years have witnessed a revolution in the fundamental understanding of disease etiology. Such knowledge gave rise to targeted therapies meant to prevent or ameliorate disease selectively while minimizing damage to normal cells and tissues. The concept of rational drug design was initiated by a handful of pioneers, including Gertrude Elion, George Hitchings and James Black in the latter half of the 20th Century [1,2]. These investigators demonstrated that knowledge of the identity and function of particular targets can be implemented to design and test new medicines. This fostered a revolution in rational drug design to identify crucial molecular targets that can be perturbed (either increasing or decreasing function) to prevent or reverse disease and/or symptoms [3]. The present study sought to assess the mechanistic basis of all new molecular entities (NMEs) approved by the FDA, with emphasis on
relating targets to therapeutic application. To accomplish this goal, the targets for all NMEs, approved as of the end of 2013 (1453 in total), were compiled and assessed using current knowledge of the modes of action. The mechanism and targets for each NME were assessed by literature reviews of multiple sources, including publically available information provided to the FDA during the review process (http:// www.fda.gov/) as well as information from PubMed (National Center for Biotechnology Information, Bethesda, MD, USA), DrugBank (The Metabolomics Innovation Center, University of Alberta, Edmonton, Alberta, Canada), SciFinder (American Chemical Society, Washington, DC, USA) and other online resources. For each NME in which a target has been identified, the target family was also catalogued. All target families containing at least five NMEs are shown (Fig. 1). The identities of the ten most common target families account for more than
three-quarters (78%) of all FDA-approved NMEs. G-protein-coupled receptors (GPCRs) constituted the largest grouping of targets, capturing more than one-quarter of all NMEs. The most commonly targeted GPCRs included adrenoceptors (78 NMEs) and cholinergic receptors (61 NMEs). Membrane channels and transporters were the second largest target class (211 NMEs), followed by targets involved in nuclear signaling (107 NMEs), proteases (67 NMEs) and oxygenases (52 NMEs).
Prominent target families Following up on the general observations about families targeted by FDA-approved NMEs, certain families were examined in greater detail. Specifically, the mechanistic basis of drug action was related to clinical indications and questions were asked as to how target prosecution has changed over time. The three largest families (GPCR, channels and transporters, and nuclear
www.drugdiscoverytoday.com Please cite this article in press as: Kinch, M.S. et al. Target selection for FDA-approved medicines, Drug Discov Today (2014), http://dx.doi.org/10.1016/j.drudis.2014.11.001
1359-6446/06/$ - see front matter ß 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.drudis.2014.11.001
Features PERSPECTIVE
The biopharmaceutical industry translates fundamental understanding of disease into new medicines. As part of a comprehensive analysis of FDA-approved new molecular entities (NMEs), we assessed the mechanistic basis of drug efficacy, with emphasis on target selection. Three target families capture almost half of all NMEs and the leading ten families capture more than three-quarters of NME approvals. Target families were related to their clinical application and identify dynamic trends in targeting over time. These data suggest increasing attention toward novel target families, which presumably reflects increased understanding of disease etiology. We also suggest the need to balance the ongoing emphasis on target-based drug discovery with phenotypic approaches to drug discovery.
1
DRUDIS 1532 1–6 PERSPECTIVE
Drug Discovery Today Volume 00, Number 00 November 2014
(a)
Targetclass
NME
GPCR Adrenoceptor (78) Acetylcholinereceptor(61)
397
Channel Sodiumchannel(49) GABA(41)
147
Nuclearsignaling Glucocorticoidreceptor(37) Estrogenreceptor(17)
104
Protease Thrombin(14) Acetylcholine esterase(12)
66
Transporter Norepinephrine (15) Serotonin(15)
65
Transpeptidase Penicillin-bindingprotein(54)
54
Oxygenase Cyclooxygenase(28) Monoamineoxidase (8)
52
Polymerase DNApolymerase(20) RNA polymerase(17)
45
Kinase Tyrosinekinase (35) Serine/threonine kinase (4)
43
Cytokine Interferon (10) Interleukin(7)
37
(b) Targetclass
NME
Ribosome
34
Synthase
32
Isomerase
31
Alkylating agent
23
Sterol
20
Esterase
19
Reductase
19
Dehydrogenase
12
Enzyme replacement
11
Tubulin
10
Celladhesion
7
Anhydrase
6
Carboxylase
6
Chelator
6
Transferase
5
Amidase
5
Othertarget
102
Unclear mechanism
95
Features PERSPECTIVE
Drug Discovery Today
FIGURE 1
Target classes for FDA-approved new molecular entities. The targets for all FDA-approved new molecular entities (NMEs) were identified and grouped into the 23 classes indicated. For the leading ten targets (a), the two most popular target subfamilies were also identified, along with the number of NMEs targeting them (in parentheses). (b) Additional prominent target families are shown, along with the number of NMEs targeting each.
receptors) were assessed first given their prominence, collectively encompassing almost half (47%) of all NMEs approved by the FDA. Each of the three largest families has persistently been targeted since the beginning of the modern drug discovery era (in the early 1950s) (Fig. 2a). At present, an average of almost five NMEs targeting GPCRs is approved each year. Likewise, almost two NMEs targeting channels and transporters and nuclear receptors are approved each year. The popularity of these three major target classes is reinforced by evidence that each has been applied to a broad array of therapeutic indications. The prominence of GPCR targets for cardiovascular indications largely reflects the role of adrenoceptor antagonists for the treatment of hypertension and beta adrenergic agonists and antagonists for cardiovascular Q2 function [5]. Herein we broaden the study to all major indications and show GPCR-modifiers dominate many other indications (Fig. 2b). 2
GPCRs are the targets for 28 of 105 (27%) of NMEs for neurological diseases, 35 of 80 (44%) NMEs approved for psychiatric indications and 46 of 63 (73%) NMEs for pain and anesthesia. The high frequency of GPCR targeting of these indications can be attributed to a handful of targets, including muscarinic acetylcholine receptor (for neurological indications), serotonin and dopamine (for psychiatric indications) and opioid receptors (for pain and anesthesia). GPCRs are underrepresented in terms of NMEs for infectious diseases, capturing five of 293 (2%) NMEs. A different subset of clinical indications were the targets of NMEs that modify ion channels (Fig. 2c) and nuclear receptors (Fig. 2d). Specifically, NMEs targeting ion channels were common for NMEs approved for pain and anesthesia (33 of 63; 52%), neurological (39 of 105; 37%) and sleeping (12 of 27; 44%) disorders. These findings include the development of local anesthetics that target sodium channels as well as
GABA agonists as sedatives [7,8]. Targeting of nuclear receptors tended to emphasize immunological (40 of 173; 23%) and hormone and reproductive (32 of 75; 43%) applications, reflecting the prominence of steroidal elements such as glucocorticoid as well as estrogen and progesterone receptors, respectively. Beyond evaluating the most common target classes, we sought to identify trends over time. Transpeptidases and isomerases were transiently popular (Fig. 3a). Transpeptidases and isomerases were most commonly utilized as targets for infectious diseases (Fig. 2b). All 58 transpeptidase-based NMEs target bacterial pathogens [9]. Their rise and decline reflects the emergence of beta-lactam-type antibiotics in the decades following 1960 and the abrupt decline in antibiotic research during recent years [10,11]. The popularity of other target families has also grown in recent years (Fig. 3c). As detailed previously, kinase-based targeting has come to dominate oncology [12]. This trend began in the
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FIGURE 2
G-protein-coupled receptors (GPCRs), channels and nuclear receptors. (a) The average annual approval rates for new molecular entities (NMEs) targeting the indicated target families is shown on a decade-by-decade basis. The clinical indications for each NME are shown for (b) GPCRs, (c) ion channels and transporters and (d) nuclear receptors.
1980s and that 75% of kinase inhibitors target Q4 cancer (data not shown). Another distinguishing
feature of the current study is a demonstration that most kinase inhibitors (35 of 43; 81%) are directed at tyrosine kinases (Fig. 1a). Cytokine-based medicines also rose with the growth in kinase inhibitors, (Fig. 3c). The first recombinant interferon was approved in 1986 for treatment of viral infections [13]. Since that time, the use of cytokines has increased, in terms of the target families as well as the indications, including use for the treatment of bone maladies (seven of 27; 26%), immunological disorders (17 of 173; 10%), oncology (nine of 170; 5%) and infectious diseases (seven of 293; 2%) (Fig. 3d). The prominence of cytokine targeting peaked at two NMEs per year in the first decade of the new millennium and has decreased in recent years. It is too early to determine whether this suggests that targeting of cytokines, like that of isomerases and transpeptidases, has peaked and is now declining.
Protease-based targeting has also grown in popularity in recent years [14]. At present, an average of four NMEs targeting proteases is approved each year (Fig. 3c). Protease targeting has grown dramatically since the 1990s. The initial wave of protease approvals largely reflects the success of modifiers of angiotensin-converting enzyme, a protease regulating blood pressure [15]. Subsequent breakthroughs in molecular modeling and therapeutic challenges surrounding the HIV pandemic facilitated the development of a series of selective inhibitors of HIV (ten NMEs) [16] and later hepatitis C virus (HCV) proteases (three NMEs). Beyond viral applications, targeting of proteases is now shared among many therapeutic indications including additional cardiovascular and infectious diseases, as well as metabolic disorders and oncology (Fig. 3d). It is easy to forget that, for many medicines approved in the time period ranging from the 1930s through the 1980s, the fact that a protease
was being targeted was unknown or unexpected. In hindsight, we are able to establish these relationships. Thus, the mechanistic analyses of FDA-approved NMEs herein is based on current knowledge of drug activity and target function, often revealed well after a drug has reached the market. A widely held view is that regulatory approval for a new medicine requires fundamental understanding of drug activity and target function in diseased and normal cells. The rationale is to maximize efficacy and minimize toxicity by targeting pathways that are most relevant to the disease while avoiding those that could be important for normal (nondiseased) cell survival or function. One can argue this approach increases the efficacy and safety of new medicines, thereby reducing the likelihood of unanticipated side-effects (e.g. those encountered post-approval with thalidomide or rofecoxib). Indeed, the rational design of HIVprotease inhibitors provided a benchmark for establishing relatively safe and effective
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FIGURE 3
Changing emphasis on target families over time. (a) The average annual approval rates for target families that (a) peaked in popularity and subsequently declined or (c) are undergoing growth is shown. (b,d) The therapeutic applications of these new molecular entities (NMEs) are indicated. Please note that the growth of kinase-based drugs for oncology is reviewed elsewhere [12].
therapeutic strategy [17]. Rational design assumes one has accurate knowledge of the most effective targets and can implement this to design ideal medicines [18] and could eliminate the serendipity often associated with phenotypic strategies that conveyed many successful medicines [19]. Indeed, a recent study emphasizes the success of phenotypic approaches as compared with target-based design [20]. The database of FDA-approved drugs was analyzed to assess those NMEs, where the mechanistic basis of efficacy remains unclear or controversial (Fig. 4a). The targets or mechanisms for 95 NMEs remain unclear (Fig. 1b). Viewed over time, the rate of approval for NMEs with an uncertain mechanism has remained stable (Fig. 4a) and has been applied to many different indications (Fig. 4b). This outcome was unexpected in light of the emphasis on rational design over the past few decades. One might have predicted that the fraction of approvals of drugs with unknown mechanism would decrease as our understanding of drug targets increases. 4
Whereas the work above contrasted wellestablished versus unknown targets, the final set of studies looked beyond the largest target families (Fig. 4c). All NMEs recognizing targets beyond the leading 20 families were collected and evaluated as a surrogate for novelty. When viewed over time, approval of NMEs recognizing these ‘other’ targets has increased steadily (Fig. 4c). In the 1950s only 1% of NMEs recognized targets outside the 23 families. This now represents 16% of NMEs approved in the current decade. Likewise, less conventional target families are broadly distributed among many indications (Fig. 4d). These are optimistic signs suggesting that increased understanding of disease is translating into novel therapeutics.
Concluding remarks The major finding of our present study is an assessment of the breadth of molecular targets recognized by FDA-approved therapeutics. Ten target families capture more than three-quarters of all NMEs. Three families alone (GPCRs, channels and transporters, and mediators of nuclear
signaling) account for almost one-half of all FDAapproved NMEs. The emphasis on target families has changed over time. Whereas the ‘big three’ families have consistently been the focus of new drug development, emphasis on other families has varied over time. Mechanisms unique to antibacterial agents rapidly peaked and declined and thus are reflective of overall declines in new antibiotic development [10,11]. Other target families, such as kinases and proteases, are in the midst of a renaissance. Both families are undergoing steady growth, in terms of the absolute number of approvals as well as their breadth of application to different disease types. Cytokine-based drugs could be arriving at a crucial inflection point. This family of targets grew in popularity from the 1980s through 2010. Data from recent years could indicate that cytokine-based drugs have peaked and are beginning to decline (similar to that observed with transpeptidases more than a decade ago), although it remains to be determined if this simply reflects an unrepresentative slow start in the current decade or whether such a trend persists.
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The dominance of the largest three target families is worthy of further consideration. Clearly, these molecules present tractable targets. Past successes with one target probably inspired additional interest in the same or related molecules, which has been described as ‘creating a herd mentality’ [21]. Given such successes, it could be that the chemical libraries that are utilized to screen new targets are influenced by, and perhaps biased toward, such targets [22,23]. This would seem a reasonable expectation because the human genome is thought to encode an estimated 400 GPCRs [24], 232 ion channels [25] and 817 transporters [26]. Thus, the yield of new medicines might just be beginning. Extending this logic, opportunities for future targeting of nuclear receptors might not be as sustainable. The human genome encodes for 48 nuclear receptors [27] and these are targeted by 107 different NMEs. Whereas incremental improvements in nuclear receptor targeting are undoubtedly possible (e.g. by improving affinity or selectivity), this family is probably closer to saturation. Thus, future growth might not remain at the level of one or
two new annual approvals, which has persisted each year since the early 1950s. Increasing emphasis on new target families suggests new knowledge of disease biology is translating into new medicines. Such results suggest sustainability of new, and hopefully orthogonal, medicines. It is worth repeating that our studies herein utilize current information about target families, which illuminates the mechanism of past NMEs. At the time of approval, the mechanistic basis of many NMEs was unknown or unclear. In this context, it is important to remember that successful medicines, many of which are still considered safe and effective today, were derived from such an approach. Although rational drug design has also proven effective [28], it will be important to identify a healthy balance between rational design of known targets versus those identified by phenotypic screens and other approaches, collectively known as forward pharmacology, where the mechanistic basis of efficacy and toxicity might not yet be clear. Such a balance could avoid potential problems resulting from inaccurate perceptions about the most
important pathways at any given time for particular indications. One might argue that phenotypic strategies can serve to identify novel targets and pathways and thereby favor subsequent generations of rationally designed drugs. Thus, the two approaches can work together hand-in-hand to ensure continued innovation.
Uncited references
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[4,6].
Acknowledgments This work was conducted as part of a project at the Yale Center for Molecular Discovery (http:// ycmd.yale.edu/) to develop a collection of all FDA-approved small molecules as a resource for screening to emphasize drug repurposing. Please contact the authors if you or your organization would be interested in potential participation in this project. References 1 Elion, G.B. (1993) The quest for a cure. Ann. Rev. Pharmacol. Toxicol. 33, 1–23 2 Black, J. (1989) Drugs from emasculated hormones: the principle of syntopic antagonism. Science 245, 486–493
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FIGURE 4
Ambiguity and novelty in drug targeting. (a) The average annual approval rates for new molecular entities (NMEs) in which the mechanistic basis is unclear is shown on a decade-by-decade basis. (b) The clinical indications for each NME are indicated. (c) The approval rates and (d) therapeutic applications of NMEs recognizing novel target families (fewer than five representative NMEs) is indicated.
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3 Foye, W.O. et al. eds (2008) Foye’s Principles of Medicinal Chemistry, Lippincott Williams & Wilkins 4 Kinch, M.S. et al. (2014) An overview of FDA-approved new molecular entities: 1827–2013. Drug Discov. Today 19, 1033–1039 5 Cruickshank, J.M. (2010) Beta blockers in hypertension. Lancet 376, 415 author reply 415–416. 6 Kinch, M.S. et al. (2014) Trends in pharmaceutical targeting of clinical indications: 1930–2013. Drug Discov. Today doi: 10.1016/j.drudis.2014.05.021 7 Reves, J.G. et al. (1982) Calcium entry blockers: uses and implications for anesthesiologists. Anesthesiology 57, 504–518 8 Haefely, W. et al. (1975) Possible involvement of GABA in the central actions of benzodiazepines. Adv. Biochem. Psychopharmacol. 14, 131–151 9 Pestka, S. (1976) Insights into protein biosynthesis and ribosome function through inhibitors. Prog. Nucleic Acid Res. Mol. Biol. 17, 217–245 10 Kinch, M.S. et al. (2014) An analysis of FDA-approved drugs for infectious disease: antibacterial agents. Drug Discov. Today 19, 1283–1287 11 Outterson, K. et al. (2013) Approval and withdrawal of new antibiotics and other antiinfectives in the US, 1980–2009. J. Law Med. Ethics 41, 688–696 12 Kinch, M.S. (2014) An analysis of FDA-approved drugs for oncology. Drug Discov. Today doi: 10.1016/ j.drudis.2014.08.007
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13 Baron, E. and Narula, S. (1990) From cloning to a commercial realization: human alpha interferon. Crit. Rev. Biotechnol. 10, 179–190 14 Hooper, N.M., ed. (2002) Proteases in Biology and Medicine, Portland Press 15 Barger, A.C. (1976) Converting enzyme inhibition and blood pressure regulation. Agents Actions 6, 538–542 16 Meek, T.D. and Dreyer, G.B. (1990) HIV-1 protease as a potential target for anti-AIDS therapy. Ann. N. Y. Acad. Sci. 616, 41–53 17 Seelmeier, S. et al. (1988) Human immunodeficiency virus has an aspartic-type protease that can be inhibited by pepstatin A. Proc. Natl. Acad. Sci. U. S. A. 85, 6612–6616 18 Johnson, K.A. and Brown, P.H. (2010) Drug development for cancer chemoprevention: focus on molecular targets. Semin. Oncol. 37, 345–358 19 Lee, J.A. and Berg, E.L. (2013) Neoclassic drug discovery: the case for lead generation using phenotypic and functional approaches. J. Biomol. Screen. 18, 1143–1155 20 Swinney, D.C. (2013) Phenotypic vs. target-based drug discovery for first-in-class medicines. Clin. Pharmacol. Ther. 93, 299–301 21 Zanders, E.D., ed. (2011) The Science and Business of Drug Discovery: Demystifying the Jargon, Springer 22 Akella, L.B. and DeCaprio, D. (2010) Cheminformatics approaches to analyze diversity in compound screening libraries. Curr. Opin. Chem. Biol. 14, 325–330
23 Hert, J. et al. (2009) Quantifying biogenic bias in screening libraries. Nat. Chem. Biol. 5, 479–483 24 Bjarnadottir, T.K. et al. (2006) Comprehensive repertoire and phylogenetic analysis of the G proteincoupled receptors in human and mouse. Genomics 88, 263–273 25 Jegla, T.J. et al. (2009) Evolution of the human ion channel set. Comb. Chem. High Throughput Screen. 12, 2–23 26 Alme´n, M.S. et al. (2009) Mapping the human membrane proteome: a majority of the human membrane proteins can be classified according to function and evolutionary origin. BMC Biol. 7, 50 27 Robinson-Rechavi, M. et al. (2001) How many nuclear hormone receptors are there in the human genome? Trends Genet. 17, 554–556 28 Mavromoustakos, T. et al. (2011) Strategies in the rational drug design. Curr. Med. Chem. 18, 2517–2530
Michael S. Kinch1, Denton Hoyer2, Eric Patridge2, Mark Plummer2 1 Washington University in St Louis, St Louis, MO, USA 2 Yale Center for Molecular Discovery, West Haven, CT, USA
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