PERSPECTIVE PHARMACOLOGY indications (such as in the case of pregaba- lin, an antiepileptic drug that was also found The NCGC Pharmaceutical Collection: to be useful for treating neuropathic pain) (6–8) or the withdrawal of marketing autho- A Comprehensive Resource of Clinically rization (which occurred for fen uramine, originally used to suppress appetite but Approved Drugs Enabling Repurposing and then found to lead to cardiotoxicity) (9, 10). Extension of the clinical use of a drug to a Chemical Genomics new indication has historically occurred via serendipitous clinical observation (for ex- Ruili Huang,* Noel Southall,* Yuhong Wang, Adam Yasgar, Paul Shinn, ample, the observation that sildena l, which Ajit Jadhav, Dac-Trung Nguyen, Christopher P. Austin was developed for treating hypertension, was also useful for treating erectile dysfunc- Small-molecule compounds approved for use as drugs may be “repurposed” for new tion) but more recently has occurred via a indications and studied to determine the mechanisms of their bene cial and adverse logical connection of a disease’s pathophysi- e ects. A comprehensive collection of all small-molecule drugs approved for human ology to a drug’s target. Examples of this sce- use would be invaluable for systematic repurposing across human diseases, particularly nario include (i) losartan, a drug developed for rare and neglected diseases, for which the cost and time required for development of a new chemical entity are often prohibitive. Previous e orts to build such a compre- to treat hypertension that might also be use- hensive collection have been limited by the complexities, redundancies, and semantic ful for treating Marfan syndrome because of inconsistencies of drug naming within and among regulatory agencies worldwide; a lack its e ects on transforming growth factor–β, of clear conceptualization of what constitutes a drug; and a lack of access to physical which plays a role in this condition, and (ii) samples. We report here the creation of a de nitive, complete, and nonredundant list of thalidomide for treating multiple myeloma all approved molecular entities as a freely available electronic resource and a physical (see below) (11–13). In general, these ef- collection of small molecules amenable to high-throughput screening. fects can be the result of the interaction of the drug on its intended target in a di er- on March 5, 2012 ent organ (which was the case for sildena l) (14) or the action of the drug on a di erent INTRODUCTION placed on drugs already approved for clini- target (so-called “o -target” e ects) and can e sequencing of the human genome and cal use. Nowhere has this attention been be bene cial (for example, imatinib—de- subsequent translational research e orts greater than in rare and neglected diseases signed to inhibit the hyperactive BCR-ABL have brought about unprecedented oppor- (RNDs), for which the expected limited protein in chronic myelogenous leukemia— tunities for the rapid application of new return on investment makes NCE develop- also acts on a harmful variant of c-kit that is biological knowledge to improve human ment particularly challenging. associated with mastocytosis) (15) or harm- stm.sciencemag.org health. Although the development of diag- Rare diseases are de ned by the U.S. Or- ful (for example, cisapride—which acts as a nostic applications of genomic information phan Drug Act as those with a prevalence serotonin receptor agonist and was formerly has been relatively straightforward, advanc- of <200,000 in the United States; although used to treat gastrointestinal problems— es in therapy have been slower, in part a re- rare diseases are frequently neglected in also a ects a cardiac potassium channel, sult of the time (10 to 15 years) and expense drug development because of their low causing cardiac side e ects) (16). (~$1 billion) of new drug development (1). prevalence, the term “neglected” diseases e case of thalidomide is a particularly New chemical entities (NCEs)—drugs generally refers to tropical diseases that may striking example of repurposing. alido- that do not contain any previously approved be highly prevalent but occur in developing mide (12, 13) was originally introduced in Downloaded from active moieties—are the focus of most drug nations that are unable to a ord treatments the late 1950s as a sedative drug and an e ec- development e orts, partly because of the (2). ere are over 6000 RNDs, of which tive antiemetic and was used widely to treat need for marketing exclusivity provided by fewer than 300 have any therapy currently morning sickness. It was withdrawn later patents to recoup the cost of drug research available (3). As a result, particular inter- because of teratogenicity and neuropathy. and development. However, the propensity est has arisen in nding drugs for RNDs in Recently, there has been growing interests of drugs to act on more than one target—or the current pharmacopeia by nding new in thalidomide because it has been found to act on their intended target in an unan- therapeutic indications for already approved e ective against leprosy and multiple my- ticipated system—has long been noted to drugs—a process frequently referred to as eloma through inhibition of tumor necrosis occur with regularity in clinical medicine, “repurposing.” factor–α and angiogenesis. e U.S. Food manifesting as either additional therapeutic A drug must be demonstrated to be rea- and Drug Administration (FDA) approved uses for a drug or adverse events. With the sonably safe and e ective in the treatment the use of thalidomide for the treatment of recent di culties of the biopharmaceutical of a disease or condition in order to receive lesions associated with erythema nodosum industry in developing NCEs, and the fo- regulatory approval (4, 5). However, when leprosum (in which fat cells under the skin cus on drug safety, more attention has been used in larger populations many drugs are are in amed) in 1998 and granted acceler- subsequently discovered to have clinical ated approval in 2006 for thalidomide in National Institutes of Health (NIH) Chemical Genomics Center, NIH, Bethesda, MD 20892, USA. utility or toxicity not appreciated at the time combination with dexamethasone for the *These authors contributed equally to this work. of approval. is phenomenon can result in treatment of newly diagnosed multiple my- Corresponding author. E-mail: [email protected] the expansion of a drug’s clinical use to new eloma patients. Studies are currently under www.ScienceTranslationalMedicine.org 27 April 2011 Vol 3 Issue 80 80ps16 1 P e r s P e ctive way to determine the effect of thalidomide a large and diverse collection of bioactive research and clinical communities, we re- on arachnoiditis—inflammation of a mem- compounds. Although most such com- solved to make the information available brane that protects central nervous system pounds have been shown to be active only through our Web site (26) and the collection nerves—and several other types of cancers. in cell-free, cell-based, or animal model sys- available to collaborators who wish to bring An alternative approach to repurposing, tems, a small percentage have been tested in, their projects to the NCGC. This Perspective which does not require a priori knowledge or approved for, use in humans and animals. describes our creation of the NCGC Phar- of a disease or drug mechanism, is to screen These latter compounds, for which we re- maceutical Collection (NPC)—a definitive drugs for activity in cell-based models of serve the term “drugs,” make up the class of collection of drugs registered or approved disease. For example, using such an ap- bioactive small molecules that might be use- for use in humans or animals—as both an proach the antibiotic ceftriaxone was de- ful for repurposing applications. A compre- Informatics and a Screening Resource and termined to represent a possible treatment hensive understanding of the activities of all delineates our approach to profiling the ac- for amyotrophic lateral sclerosis (17), and drugs in the pharmacopeia would facilitate tivity of this collection across a broad array the antihistamine astemizole was identi- the greatest possible application of known of human pathways and diseases. This on- fied as a potential antimalarial drug (18). drugs across the full spectrum of human going project will benefit the medical, sys- These anecdotal successes raise the possi- diseases and help explain or predict their tems biology, and toxicology communities bility that a substantial percentage of RNDs toxicities. via the NPC Informatics Resource browser might be treatable with drugs in the current In order to enable this systematic drug (Fig. 1), which we describe here (26), and pharmacopeia. Biopharmaceutical compa- mechanism and repurposing effort, we de- via the NCGC’s collaborative screening pro- nies understandably have been grams. Data on the activities of less enthusiastic about testing these drugs generated through their drugs for these indications screening of the NPC Screening because if such drugs are still Resource will be made publicly covered by patents, any adverse available through PubChem events in RND patients could (27), with links provided on adversely affect revenue, and if the NPC Informatics Resource on March 5, 2012 the drugs are generic, the new browser. RND indication would provide little financial return. Academic WhaT IS a “DRUg”? investigators or disease foun- Approval of a drug for human dations may be interested in use is assumed to be an unam- pursuing this approach but fre- biguous event, so when we em- quently lack the infrastructure barked on this comprehensive and expertise to do so. Even drug collection project we were stm.sciencemag.org when such approaches are suc- surprised to find that estimates cessful, the data are generally of the number of approved not aggregated with those from drugs in the literature vary other assays (preventing cross- widely (18, 22, 28).