Inhe MIM)(for genen es).Analyse arthritis,mul e scler Abh and oth d to the ar the findings that only a fev he othe au mains d thera eutic d s b)th antil the drug polyp eains it is int to note that curr HER Th emis to design and ica's Bio harmac that it ha othe ers)in ent (Pha sI-I an app appro its p of drug Serg 12010 Cla fied in se ets d ing (GPCRs T egor xidoreduc (1).and other groups (2).Within the trar oltage-gal 00 channels(29).oth cs(total90 in clin cal de (1 porters (3). and auxiliar tra nerica's Bic 2 d by the FDAli D that e than 100 diseases (cance r.38;infectious disea rate of s n of targets over th thers in ng diabe and digestive.genetic. s to pus e"hi is i dramatic incr thcare to new he ghts Identifyi which t of the rug d nd hat aturel d tempt s for temoe are currently being hotly p Most of the drue d ne19s22010e ng th and inclu argeting r sand na n the mea h ver.the numbers of biologic drugs ength.for each approach has its own I an ncrea in the las对 and enym g a mor than f le trend has emerged last few years a d by the CD20 B-h mphocyte antigen.used to treat rheumatoid ed against the mutant BRC-ABL kinase and used for the Chem.mtEd2014..9128-914 ndte org 93 Inheritance of Man (OMIM) (for genetic diseases). Analyses of data from these databanks reveal interesting facts and trends. Among them are a) the findings that only a few hundred targets, and even fewer privileged druggable do￾mains, account for all the approved therapeutic drugs, b) the emergence of target families [gene families, e.g., protein kinases, G protein coupled receptors (GPCRs)], and c) the recognition of the importance of drug polypharmacology (binding to and modulation of several targets).[6] In this respect, it is interesting to note that current knowledge places the number of human genes to 25 000, human proteins to 200 000, and human cells to 12 trillion.[39] The task of the medicinal chemist to design and synthesize a molecule that would navigate selectively to its target is enormous. The fact that it has been done so many times is a tribute to medicinal chemists and those other scientists that contributed so brilliantly to bring the state of affairs in drug discovery to its present admirable condition. Recent analyses of drug targets and their ligands revealed further useful intelligence and insights.[16] Thus, up to 2010, 435 effect-mediating biological targets in the human genome were modulated by 989 drugs through 2242 binding inter￾actions.[16] Classified in several groups, these targets include the families of receptors (193), enzymes (97), transporter proteins (67), and others (51). Among the latter group are enzyme-interacting proteins, structural and adhesion proteins, and ligands. The receptor group includes G protein coupled receptors (GPCRs, 82), ligand-gated ion channels (39), tyrosine kinases (22), immunoglobulin-like receptors (21), nuclear receptors (17), and other receptors (12). The enzyme category includes the families of oxidoreductases (22), trans￾ferases (21), hydrolases (43), lyases (3), isomerases (5), ligases (1), and other groups (2). Within the transporter protein class are the voltage-gated ion channels (29), other ion channels (6), solute carriers (12), active transporters (7), other trans￾porters (3), and auxiliary transport units (10). Database analyses also revealed that from 1982 to 2010, a total of 520 drugs were approved by the FDA.[16] Derived from these studies were also the conclusions that most of these drugs operate on previously targeted human proteins, and that the rate of successful modulation of targets over the last 30 years has been stable. In the last few decades only a few new “druggable” biological targets have emerged each year. This is in contrast to the rather dramatic increase in investment and despite the impressive advances made in biology and chemistry over this period. This dissymmetry may be traced to a number of reasons, including the aforementioned “low￾hanging fruits” explanation, pressures to deliver drug candi￾dates prematurely, and temptations for temporary gains at the drug candidate optimization phase vs. long-term benefits. Most of the drugs discovered in the 1982–2010 period were small molecules and include those targeting novel biological targets. In the meantime, however, the numbers of biologic drugs such as monoclonal antibodies, fusion proteins, and enzymes have been steadily increasing in the last two decades, demonstrating a more than fashionable trend. These include antibodies [for example, rituximab (Rituxan, Roche; binds to CD20 B-lymphocyte antigen, used to treat rheumatoid arthritis, multiple sclerosis, and other autoimmune diseases), adalimumab (Humira, Abbott; binds to TNFa, used to treat rheumatoid arthritis and other autoimmune diseases) and trastuzumab (Herceptin, Genentech; used against HER2 positive breast cancer)] and antibody drug conjugates (ADCs) with cytotoxic drugs as payloads for targeted cancer chemotherapy [e.g., brentuximab vedotin (Adcetris, Seattle Genetics and Millenium/Takeda; used against advanced Hodgkins lymphoma) and trastuzumab emtansine (Kadcyla, Genentech/Roche; used against late-stage HER2 positive breast cancer)]. Biologics will continue to be on the rise as drugs and drug candidates. Indeed, a recent report from Americas Biopharmaceutical Research Companies[39] lists 907 biologic drug candidates (antisense, cell therapy, gene therapy, monoclonal antibodies, recombinant proteins, vac￾cines and others) in clinical development (Phases I–III and pending application for approval, see Figure 2). Targeting more than 100 diseases (cancer, 38; infectious diseases, 176; autoimmune diseases, 71; cardiovascular diseases, 58; and others, including diabetes and digestive, genetic, neurologic, and respiratory disorders), these drugs promise to push the frontiers of science and medicine to new domains and advance healthcare to new heights. Identifying which drugs will help which patients and following up with personalized medicines is clearly the new paradigm in medicine and will certainly contribute to the improvement of the drug discovery and development process and better healthcare for the patients. While biologics are currently being hotly pursued, we should not allow the success of any given modality to swing the pendulum too far in one direction and certainly not away from small molecules and natural products. Indeed the complementarity of each approach should be exploited and viewed as a strength, for each approach has its own advantages and disadvantages. Another powerful trend, that of multitargeting drugs,[40, 41] has emerged over the last few years as marked by the introduction of imatinib (Gleevec, Novartis). Initially target￾ed against the mutant BRC-ABL kinase and used for the Figure 2. Number of biologics (total 907) in clinical development (phases I–III and approval process) by product category (2013 report from America’s Biopharmaceutical Research Companies).[39] Angewandte Chemie Angew. Chem. Int. Ed. 2014, 53, 9128 – 9140 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org 9131