The NCGC Pharmaceutical Collection

PERSPECTIVE

PHARMACOLOGY indications (such as in the case of pregabalin, 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 IN TRODUCTION 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). The FDA assay comparisons) or made does not maintain a single list of Fig. 1. The NPC database browser. this browser (26) provides users public (preventing the use of the with a graphical interface with which to explore drugs by a number of drugs that they have approved; data by others). Both activities attributes, including but not limited to name, structure, approval status, instead, there are several such would probably reveal impor- indication, and target information. listings, each with its own par- Downloaded from tant relationships among dis- ticular legal origin, intent, and eases and drug targets. limitations. The United States The National Institutes of Health (NIH) sired to identify and then acquire the com- Pharmacopeia (USP)–National Formulary, Chemical Genomics Center (NCGC) is a plete, nonredundant collection of small- which is published by the nongovernmen- national resource for the translation of infor- molecule drugs approved for human or tal organization USP, is cited by the Fed- mation found in the genome into biological veterinary use by regulatory agencies world- eral Food, Drug, and Cosmetic Act of 1938 insights and new therapeutics, particularly wide. However, upon initiating this effort as the official compendium of the United for RNDs (19, 20). The NCGC collaborates it rapidly became evident that neither such States but is incomplete (29). The FDA pub- with disease and target experts worldwide to a complete nonredundant list of drugs nor lishes several official lists of its own, includ- develop chemical probes for previously un- such a physical collection of them existed. ing (i) the Orange Book, (ii) the National studied biological and therapeutic systems, Several attempts have been made to compile Drug Code (NDC), (iii) the Drugs@FDA using its assay development, quantitative such a collection (21–25), but upon scrutiny Web page, (iv) the Over-the-Counter (OTC) high-throughput screening (HTS), infor- all turned out to be incomplete and/or to listings from the Office of Nonprescription matics, and medicinal chemistry platforms contain bioactive compounds not approved Products, and (v) its Substance Registra- (20). As part of its chemical genomics pro- for use in humans. We therefore resolved tion System’s Unique Ingredient Identifier gram aimed at understanding the features to assemble a definitive collection. Because (UNII) (30). An August 2006 Department of small molecules that are important for this task only needed to be done once and of Health and Human Services, Office of biological activity, the NCGC has assembled would be an enormous resource for the Inspector General audit of the NDC found

www.ScienceTranslationalMedicine.org 27 April 2011 Vol 3 Issue 80 80ps16 2 PERSPECTIVE on March 5, 2012 stm.sciencemag.org

Fig. 2. What’s in a name? Deﬁ nitions of the terms Drug Product, Drug, API, and ME and the numbers associated with each term. Record counts include veterinary drugs. Numbers of substances approved only for human use are shown in parentheses. The deﬁ nition of an API comes from (74), and that of a chemical entity (CE) comes from (75). CGMP, current good manufacturing practices. Downloaded from that over 14,000 drug products were missing cisely de ning the term did the number and paroxetine mesylate and paroxetine hydro- from o cial government registries and that identity of all substances to be included in chloride). Although di erent APIs of the over 34,000 listed products were no longer our comprehensive collection become clear. same ME may exhibit distinct absorption, being marketed (31). FDA has acknowl- For the purpose of pharmacologic, distribution, metabolism, excretion, and edged these informatics shortcomings and mechanistic, and repurposing studies, the toxicity (ADMET) properties in vivo, this has recently introduced an initiative to cor- term “drug” refers to a molecular entity distinction is rarely relevant for in vitro and rect this issue (32, 33), but that work has (ME) (40) that interacts with one or more in silico studies, so the NPC Screening Re- not yet been completed. Several others have molecular targets and e ects a change in bi- source contains only one API for each ME. also attempted to generate a precise listing ological state. ese may be small molecules, Next on the scale of lexical speci city of FDA-approved drugs (34–39). Compar- proteins, antibodies, or other substances (Fig. 2) is the term “Drug” as it is used by ing these resources, we discovered that none such as small interfering RNAs or aptamers. FDA, which is a name approved for market- of these lists fully concur with one another, is term unambiguously denotes a unique ing that de nes an API or set of APIs used. probably because of varying de nitions of molecule with a known structure. us, a given API may be found in multiple

T I O N AL HUM AN G E M R S AR C H UT / the term “drug,” the complexity of the regu- e term “active pharmaceutical ingredi- drugs (for example, ibuprofen, Motrin, Ad- latory process, and the complexity of FDA’s ent” (API) refers to the molecule in physical vil, and Nuprin). is term includes drugs own publications. Research, medical, mar- form and is more speci c because di er- requiring a prescription and those that : D . L E J A/ N A keting, and lay communities use the word ent esters or salt forms of the same ME are do not [“Over-the-Counter” (OTC)], and

C R E DI T “drug” quite di erently, and it is only in pre- designated as di erent APIs (for example, those covered by current market exclusivity

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(“brand”) and those that are not (“generic”), containing product is also listed separately sitic that was rst approved for veterinary and may be small molecules, proteins, anti- in regulatory databases. us, worldwide use and subsequently repurposed for treat- bodies, or other substances or groups of sub- there are hundreds of di erent Drugs and ment of human helminthic diseases (which stances. Also included in the category that Drug Products that appear separately in involve parasitic helminth worms), par- FDA (and other regulatory agencies) terms drug databases, but all are composed of or ticularly onchocerciasis, a disease caused Drugs are substances or extracts without a contain the same ME/API, N-(4-hydroxy- by infection with a nematode that leads to de ned molecular structure and products phenyl)ethanamide. is circumstance ex- blindness (45). alidomide is a prominent that are used for supportive or diagnostic ists for many APIs, essentially none of which example of a previously withdrawn drug be- purposes but are not intended to be used as is marketed under only one name in only ing repurposed for another indication and speci c modi ers of a particular disease or one dose, form, or combination. reapproved (13). Drug withdrawal may oc- condition. ese substances include thou- cur either because FDA or another regula- sands of allergenic extracts, commonly used COMPILING COMPLETE AND tory agency withdraws marketing approval intravenous uids such as lactated Ringer’s NONREDUNDANT LISTS OF DRUG (46, 47) or because the manufacturer vol- solution and D5W (5% dextrose in water), PRODUCTS, DRUGS, APIS, AND MES untarily ceases production (for example, oxygen, and puri ed air. Assembling a comprehensive enumera- mesoridazine, which was originally used to Lastly, the most speci c term for such tion. Using the de nitions above, each cat- treat schizophrenia and withdrawn because substances is “Drug Product.” Most Drugs egory was enumerated using data rst from of serious side e ects); in the latter case, the are marketed in a wide variety of dosages, the FDA and then from regulatory agencies drug may remain listed in regulatory publi- forms (for example, oral, intravenous, and outside the United States. In this step, inclu- cations. Several resources that list and mon- intramuscular), combinations, and packag- sion and completeness was the goal, with itor drug withdrawals (48–53) were includes, and each of these is referred to as a “Drug redundancy to be eliminated later (see the ed in the NPC. However, the designation Product” by FDA. following section). Lists of drug names ap- “withdrawn” is not unambiguous because ese de nitions clarify why there has proved for human use were obtained from drugs are frequently withdrawn for one in- been such confusion about what a Drug is the FDA o cial publications listed above. dication while remaining approved for oth-

and how many there are and make possible A er assigning structures and Chemical ers, or withdrawn in one country or market on March 5, 2012 the building of a comprehensive and non- Abstracts Service (CAS) numbers to these while remaining on the market in others. redundant list and collection. What the lay names wherever applicable and removing e veterinary drugs and drugs withdrawn public refers to as a Drug is more properly duplicate entries, we found that FDA has for certain indications are labeled as such in termed a Drug Product. In mechanistic re- over 100,000 Drug Products registered. the NPC browser (26). search parlance, however, Drug refers to a ese Drug Products have in them over Drugs are frequently approved in other ME, or an API when the physical substance 10,000 Drugs. However, this latter number, countries but not approved by the FDA; we is being considered. although formally correct, is misleading be- wished to capture these Drugs for the NPC e example of the common analgesic cause the majority of these 10,000 are di er- as well. We therefore performed analogous stm.sciencemag.org and antipyretic medicine Tylenol illustrates ent brands of the same API, di erent APIs de nition of terms, enumeration of catego- the importance of these distinctions to the of the same ME, or chemically unde ned ries, and de nition of structures for Drugs proper classi cation and counting of drugs. substances (for example, allergenic extracts) approved by regulatory agencies in other N-(4-hydroxyphenyl)ethanamide, which is (table S1). countries (Table 1). We obtained listings known as “acetaminophen” in the United We considered the possibility that addi- from the Dictionary of Medicines and De- States, is the API in Tylenol. However, this tional Drugs might exist that are not listed vices published by the UK National Health API is also marketed under many other by the FDA if they were in use before the Service Information Authority (NHS), brand names, each registered as a separate relevant statutes took e ect in 1938 (41). We Health Canada’s (HC) Drug Products Da- Downloaded from Drug by the FDA. ese names include could nd no evidence of such additional tabase, the European Medicines Agency Aceta, Actimin, Anacin-3, Apacet, Aspirin drugs, and FDA considers such drugs un- (EMA), and an English translation of the Free Anacin, Atasol, Banesin, Crocin, Dapa, likely (42). FDA has made e orts to evalu- Japanese Pharmacopeia, Fourteenth Edition. Dolo, Datril Extra-Strength, DayQuil, De- ate drugs in use before 1938 and has taken Whereas currently or previously ap- pon & Depon Maximum, Feverall, Few proactive steps to exclude them from the proved drugs may be those most amenable Drops, Fibi, Fibi plus, Genapap, Genebs, market if the science was found lacking, as to repurposing, compounds that have been Lekadol, Liquiprin, Lupocet, Neopap, Ny- was the case with ethyl nitrite (“sweet spirit registered for human testing but not neces- Quil, Oraphen-PD, Panado, Panadol, Para- of nitre”—a traditional remedy for colds and sarily approved by any regulatory agency len, Phenaphen, Plicet, Redutemp, Snaplets- u ) ( 43, 44). also represent potentially attractive starting FR, Suppap, Tamen, Tapanol, Tempra, Two categories of compounds not cur- points for further testing and/or medicinal Valorin, and Xcel. Each brand name also rently approved for human use were then chemistry optimization so were also includ- comes in di erent forms—such as tablet, added to this enumeration because of their ed in the NPC. is category includes unap- capsule, liquid suspension, suppository, in- potential for human application: veteri- proved Drugs registered by the U.S. Drug En- travenous, and intramuscular—and doses, nary products listed in the Green Book (the forcement Agency (DEA), compounds listed and each of these is listed as a separate Drug FDA-approved animal drug list) and drugs in the World Health Organization (WHO) Product. Outside of the United States, this previously approved for human use but International Nonproprietary Names (INN) API is known not as acetaminophen but subsequently withdrawn from the market. and United States Adopted Names (USAN) as paracetamol, and each paracetamol- Ivermectin is a broad-spectrum antipara- registries, and compounds listed on the U.S.

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Table 1. Data sources for approved drugs. tari schedule (Table 2). ese listings include Drugs that have an approved Investi- Data Source URL Country Agency Type gational New Drug (IND) application with Approved Drug Prod- http://www.fda.gov/cder/ob/ USA FDA Human the FDA or analogous approval by regulatory ucts (Orange Book) agencies outside the United States, and those FDA Oﬃ ce of Nonpre- http://www.fda.gov/downloads/ USA FDA Human that are being tested or have been tested in scription Products (OTC AboutFDA/CentersOﬃ ces/CDER/ clinical trials in humans. Importantly, inclu- Ingredient List) UCM135691.pdf sion in any of these latter registries does not FDA NDC http://www.fda.gov/cder/ndc/ USA FDA Human indicate that the drug has in fact been tested Drugs@FDA http://www.accessdata.fda.gov/scripts/ USA FDA Human in humans, much less the stage of testing (for cder/drugsatfda/ example, phase I, II, or III). e latter infor- Approved Animal Drug http://www.fda.gov/AnimalVeterinary/ USA FDA Vet mation is impossible to determine systemati- Products (Green Book) Products/ApprovedAnimalDrugProducts/ cally because it is generally not disclosed by ucm042847.htm the company doing the trials; ClinicalTrials. Dictionary of Medicines http://www.dmd.nhs.uk/ UK NHS Human gov, for instance, requires prospective regis- and Devices tration of the trial but does not standardize European Public Assess- http://www.emea.europa.eu/htms/ EU EMA Human disclosure of the API (or APIs) being tested. ment Reports (EPARs) human/epar/a.htm Although not immediately useful in repur- for authorized medical posing applications, these USAN/INN drugs products for human use may be considered partially developed drugs Human medicines— http://www.emea.europa.eu/htms/ EU EMA Human and therefore require less e ort to achieve Orphan medicinal human/orphans/opinions.htm regulatory approval than do compounds in products preclinical stages of drug development. De- EPARs for authorized http://www.ema.europa.eu/ema/index. EU EMA Vet tailed information on the number of drug medical products veteri- jsp?curl=pages/medicines/landing/

records obtained from each source can be on March 5, 2012 nary use vet_epar_search.jsp found in table S1. Therapeutic Products http://www.hc-sc.gc.ca/dhp-mps/ Canada HC Human Generating a nonredundant list of MEs. Directorate prodpharma/databasdon/ Having produced an aggregate enumeration The Japanese Phar- http://jpdb.nihs.go.jp/jp14e/ Japan NHI Human that was complete, we then devised a pro- macopeia, Fourteenth monographs2.html cess to eliminate redundancy to arrive at a Edition list that was nonredundant—in which each The Japanese Pharma- http://jpdb.nihs.go.jp/jp14supp1e/ Japan NHI Human ME was represented only once. ere are copeia, Supplement I multiple mechanisms by which a single ME stm.sciencemag.org The Japanese Pharma- http://jpdb.nihs.go.jp/jp14supp2e/ Japan NHI Human may be listed more than once in drug list- copeia, Supplement II ings, including by simple duplication within The Japanese Pharma- http://moldb.nihs.go.jp/jp/index.html Japan NHI Human or between countries or by listing of MEs as copeia, Name Database distinct APIs, Drugs, or Drug Products. Be- cause this redundancy is the source of much of the confusion in the literature about how Table 2. Sources for bioactive compounds (including unapproved substances) tested in many MEs exist, this process of redundancy humans. elimination is described here in some detail. Downloaded from Data Source URL Country Agency Di erent regulatory agencies o en as- sign di erent names for the same API (for DEA Drug http://www.usdoj.gov/dea/pubs/scheduling.html USA DEA Scheduling example, paracetamol and acetaminophen) and do not adhere to standard ways of list- WHO INN http://www.who.int/medicines/publications/druginfor- WHO mation/innlists/en/index.html ing active ingredients (for example, terazosin, terazosin hydrochloride, and terazosin USAN http://www.ama-assn.org/ama/pub/physician-resources/ USA AMA/ hydrochloride anhydrous are all used to re- medical-science/united-states-adopted-names-council/ USP/APhA adopted-names.page fer to the same API); such idiosyncratic and inconsistent naming made synonym iden- Harmonized http://www.usitc.gov/publications/docs/tata/hts/ USA U.S. ITC Tariﬀ Schedule bychapter/0600PHARMAPPX.pdf ti cation di cult. Several heuristics were of the United created to eliminate redundancy reliably. States Because the only completely unambiguous FDAMDD http://www.epa.gov/ncct/dsstox/sdf_fdamdd.html USA identi er was chemical structure, but the regulatory agencies did not supply structur- KEGG Drug http://www.genome.jp/kegg/drug/ Japan/ USA/ al information, APIs were matched to chem- Europe ical structures via names, synonyms, and/or CAS numbers. Structures were primarily AMA, American Medical Association; APhA, American Pharmacists Association. derived from ChemIDPlus’s PubChem de-

www.ScienceTranslationalMedicine.org 27 April 2011 Vol 3 Issue 80 80ps16 5 PERSPECTIVE posited substances (54), Prous’s PubChem was added indicating a potential error in the United States, greatly in ating the reported deposited substances (search for “Prous structure, name, or CAS. Manual curation number of “approved” drugs available for Science Drugs of the Future”[SourceName] was then performed to correct such mis- repurposing. USAN/INN listing in fact only under PubChem Substances) (27), the FDA takes (table S2). Because a unique ID was as- indicates registration by a sponsor of inten- Maximum (Recommended) Daily Dose da- signed to each unique ME, mixtures (that is, tion to le for human use at some point, but tabase (FDAMDD) (55), commercial sup- drugs made up of multiple MEs) had more not approval for any such use (62). plier catalog structures, SciFinder searches, than one unique ID assigned. How many drugs are there? i s r i g o r - or ChemO ce’s name-to-structure util- Comparison with previous estimates of ous process of de nition, enumeration, and ity (56) if an International Union of Pure drug numbers. e NPC is the most com- redundancy elimination allowed us to arrive and Applied Chemistry (IUPAC) name prehensive and accurate exposition to date at de nitive numbers of MEs, APIs, Drugs, was available, and were manually checked of MEs registered or approved for human or and Drug Products, approved for human against existing literature, including drug veterinary use worldwide. ere have been and/or veterinary use, in the United States labels (57). CAS identi ers are included in many previous e orts at compiling drug and/or other countries; these are summa- the Japanese Pharmacopeia, and were also lists, but upon examination it was evident rized in Fig. 2 and listed in detail in table obtained from ChemIDPlus via PubChem that all have su ered from substantial over- S1. Because for scienti c purposes the term and manually from SciFinder. We relied counting, undercounting, and/or misclas- “drug” is most properly used to describe on SciFinder to nd the correct mapping si cation. Much of the confusion derives MEs, the most accurate answer to the ques- from name to CAS and to structure once from di erent de nitions of what a “drug” tion, “How many drugs are there?” is in re- an inconsistency was identi ed. As a struc- is, the redundancy of drug name listings, ality “How many approved MEs are there?” ture source, commercial supplier catalogs the o en opaque nature of regulatory agen- e answer to this question is that 2356 MEs (tables S3 and S4) were found to be less re- cy databases, and the lack of a connection are approved for human use by the FDA, liable (that is, more error prone) than were of drug names to unambiguous chemical and 3936 MEs are approved for human ChemIDPlus and FDAMDD. An initial identi ers such as structures or simpli ed use in major markets worldwide including scan identi ed 1770 inconsistencies (di er- molecular input line entry speci cations (or the United States. ese will be the richest

ent structures having the same name) from SMILES). In addition, the term “approved” source for repurposing applications because on March 5, 2012 12,800 vendor records, indicating an error has previously been used in di erent ways. they are already approved for human use, rate of approximately 14%. On the basis of A compound may be “approved” for listing and thus approval of new indications will be the incorrect structures identi ed during in a database (such as the INN), “approved” most straightforward. the manual curation process, ChemIDPlus, for use in experimental settings only (as When MEs approved for veterinary use of which we curated 12,300 records linked indicated by IND approval by FDA), “ap- are included, the numbers of MEs increase to approved drugs, appeared to be a reli- proved” by one or more regulatory agencies to 2508 that are approved by FDA and 4034 able source for structures with an estimated for speci c clinical uses and marketing, or worldwide. Also, there are 4935 unique MEs error rate of 1.3% (155 errors found), and may have been previously “approved” but included in the USAN, INN, U.S. Tari stm.sciencemag.org FDAMDD, with 990 of its 1217 structures subsequently withdrawn from the market. schedule, WHO, DEA, Kyoto Encyclopedia curated, was of similar quality, with an error Compounds in all of these categories have of Genes and Genomes (KEGG) drugs, and rate of 2.0% (20 errors found). been included in previous listings of “ap- FDAMDD database listings of compounds Many compound structures included salt proved” drugs, although only a fraction can registered for experimental human use but and solvent. Common salts were removed actually be used in medical practice. In the not approved by any regulatory agency for computationally, and the remaining mix- NPC, “approved” means that marketing and marketing (table S1). Although not im- tures separated into component MEs by us- use in medical practice, for the prevention mediately useable for human applications, ing automated so ware followed by manual or treatment of one or more disease indica- these MEs would provide a “jump start” to Downloaded from curation to verify the results. As structure tions, is currently allowed by one or more new drug approvals and so are of interest representations of heavy metal–containing regulatory agencies worldwide. and importance as well. Taken together, the compounds are frequently problematic, a ese ambiguities, and the lack of meth- 4034 unique worldwide approved MEs and special set of heuristics were applied to these odological detail in many previous estimates 4935 unique worldwide registered MEs sum drugs so that any fragment without a carbon of drug listings, make comparison with to a total unique 8969 MEs, which represent or nitrogen and with less than six atoms was our results di cult. Previous estimates of the universe of compounds for repurposing, removed, and the rest of the molecule treated the number of “FDA-approved” drugs for advanced drug development, and chemical as one ME. Structures were then canonical- screening have ranged from 1382 (61) to genomics. ized to facilitate ME matching by use of the 6534 (35) and of approved drugs worldwide IUPAC International Chemical Identi er or up to 9990 (22). Scrutiny of these databases THE NPC INFORMATICS RESOURCE InChI hash key (58) and a NCGC so ware revealed undercounting of approved drugs, From these listings, we created the NPC package for structure standardization (59, misdesignation of tested drugs as approved, Informatics Resource (26), which lists all 60). To accomplish this, API records were and inclusion of the same ME more than drug MEs and APIs and whether or not they rst merged by canonical MEs, then by CAS once because of naming ambiguities. Lastly, are suitable for laboratory-based screen- number, and lastly by names and synonyms. some reports have incorrectly indicated that ing and enables informatics-based rational Each unique ME was assigned a unique compound listing in the USAN or INN in- repurposing and chemical genomics ap- ID. If more than one unique ID shared the dicates either entry into phase II clinical tri- plications. All APIs corresponding to these same CAS numbers or name, an alert ag als or approval for regulatory use outside the MEs are also included. Currently, the NPC

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Informatics Resource contains Fig. 3. Work ow for the NPC 2508 FDA-approved MEs and library construction process. 4034 worldwide-approved MEs. This process is complicated by the Including the 4935 unique MEs high prevalence of errors in the from the USAN and INN reg- data sources. Octylmethoxycin- namate is shown as a semantic istries, the NPC Informatics web diagram as an example. In the Resource contains 8969 unique diagram, each node represents MEs. Information will be pe- one entry from a data source. Lines riodically updated as curation represent identity relationships proceeds, new MEs are added as between source nodes, matching they are registered or approved, either on (i) name, (ii) CAS, or (iii) and errors are found. is pro- chemical structure. The line in red cess will bene t enormously represents a spurious synonym from community feedback, and linkage (Escalol 506) between we urge users to employ the er- padimate A and octinoxate. ror report mechanism on the site (26). Database updates with new APIs with vendor entries indi- records and error xes will be vidually (Fig. 3). In addition, released periodically with dis- di erent vendors frequently tinct database version numbers. represented a given ME with di erent structures, so so ware THE NPC SCREENING was written to detect discrep- RESOURCE ancies and resolve them auto- Laboratory-based HTS places matically whenever possible.

certain constraints on the types When resolving ambiguities, on March 5, 2012 of molecules that can be tested; ChemIDPlus (63) was particu- therefore, a subset of the NPC larly accurate and useful. Informatics Resource, termed Compound acquisition was the NPC Screening Resource, prioritized by approval status, was created for HTS applications. ease of acquisition, and cost. e NPC Screening Resource Currently approved drugs were excludes large molecules (such assigned a higher priority for as proteins and antibodies >1500 acquisition than investigational stm.sciencemag.org MW), as well as small molecules drugs, and drugs registered in that are insoluble in dimethyl the United States were assigned sulfoxide (DMSO), unstable at a higher priority than drugs reg- room temperature, have less than istered in other countries. Drugs 16 atoms, or have no carbon or were procured from commercial nitrogen atoms. Because di er- bioactive compound collections ent salt forms of the same ME be- (for example, Sigma-Aldrich’s have similarly in in vitro assays, Library of Pharmacologically Downloaded from only one API corresponding to Active Compounds) and bulk each ME was included. e APIs chemical suppliers (for exam- suitable and not suitable for HTS ple, Sigma-Aldrich and Chem- are labeled accordingly in the Bridge) rst, from which large NPC Informatics Resource (26). numbers of compounds were e NPC Screening Resource available at relatively low cost, listing includes 2750 worldwide- with structures provided for all approved MEs (including 1817 compounds. Procurement ag- FDA-approved MEs) and 4881 gregators such as ChemNavi- USAN/INN MEs, for a total of gator and specialty chemical 7631 MEs (table S1) (26). vendors (table S4) that gener- Acquisition of all approved ally supply compounds at higher drugs. Acquisition of physical costs were used next. If no com-

T I O N AL HUM AN G E M R S AR C H UT / samples of the 2750 worldwide- mercial supplier could be found approved ME/APIs on the NPC Screening IUPAC name, or CAS number, and none of for a drug, the drug product was obtained Resource list was surprisingly challeng- this information is routinely available from from pharmacies and the API puri ed. For : D . L E J A/ N A ing, principally because chemical vendors the regulatory agencies. erefore, we used compounds not available commercially,

C R E DI T generally list their inventory by structure, intermediary data sources to connect ME/ drugs were custom synthesized either by

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NCGC chemists or via outsourcing; cured or synthesized. Approximately the cost for custom synthesis depend- 20% of the remaining MEs are obtained on the structural complexity and able from chemical vendors, and the number of synthetic steps and ranged remaining 60%, totaling nearly 3000 from $1000 to $40,000 for 100 mg of compounds, will require synthesis compound. at the NCGC or via contract syn- e current acquisition status thesis (Table 3). Given the cost and of the NPC Screening Resource is time required for custom synthesis, summarized in Table 3. e major- we expect that the expansion of the ity (64%) of the NPC Screening Re- NPC Screening Resource to include source–approved drugs, totaling 1767 all registered MEs will be a long-term compounds, were obtained from e ort, but a critically important one. major suppliers, including Sigma- When considering starting points for Aldrich (St. Louis, MO), Tocris Bio- chemical optimization for a new drug, science (Ellisville, MO), MicroSource these 3000 compounds may be con- Discovery Systems (Gaylordsville, sidered advanced leads with probable CT), Enzo Life Sciences International attractive activity, physicochemical, (Formerly BIOMOL International, and ADMET properties, which may L.P., Plymouth Meeting, PA), Prest- therefore allow considerable time sav- wick Chemical (Illkirch, France), USP, ing as compared with leads generated the National Institute on Drug Abuse from conventional HTS of diversity (NIDA), and the National Cancer In- collections. stitute (NCI) (table S3). Controlled Recently, we began procuring or substances were mainly procured synthesizing (i) drugs approved in

from NIDA and Sigma, a er licensing countries or regions other than the on March 5, 2012 of the NCGC by DEA. ese suppliers United States, United Kingdom, Eu- were willing to provide compounds in rope, Canada, and Japan and (ii) ac- 96-well plate or 96-tube rack formats, tive metabolites of approved drugs. making them the easiest to prepare e building of the NPC Informatics for screening. Approximately 15% of and Screening resources will be ongo- the collection (404 compounds) were ing, and as new compounds are added sourced as individual compounds to regulatory databases, and physical from over 70 smaller chemical sup- samples are obtained, the Informat- stm.sciencemag.org pliers (table S4), either directly from ics and Screening Resource pages will the supplier or through procurement be updated on our Web site. For im- aggregators such as ChemNavigator mediate use by the community, we (San Diego, CA). is was a time-in- have listed all compounds in the NPC tensive process, requiring the iterative Screening Resource by regulatory manual compilation of a master list agency and supplier in Fig. 4 and table of compound names and structures. Fig. 4. The composition of the NPC Screening Resource. S4, as well as at the NPC Web site (26). Continual changes in vendor o erings This Resource is shown broken down by (A) regulatory Quality control of the screening Downloaded from led us to create a custom structure agency, (B) supplier type, and (C) sample cost. If a drug is resource. Ensuring the correct identi- comparison tool (MolOverlap v1.0) listed by more than one regulatory agency, it is counted ty and purity of compounds in screen- (64), which compares structure-data only once following the approval status priority rank: (i) ing collections is a critical aspect of FDA, (ii) United Kingdom/Canada/European Union/Japan, les from all vendors to a master list drawing reliable conclusions from and (iii) investigational. of structures and outputs a text le of HTS data (65). is point is particu- matching structures to be obtained; larly critical for the NPC because the this tool is freely available (64) . i s t o o l these compounds; synthesis of the remain- data generated from these compounds may allows us to rapidly, accurately, and con- ing 359 will be completed over the next 6 be used to advance new clinical applications tinuously extract updated catalog items months. and draw conclusions about the universe of and procure them for the collection. APIs Acquisition of compounds registered targets a ected by clinically approved drugs that are not commercially available were but not approved for human use. Of the and will be made publically available. ere- sourced as drugs from pharmacies and pu- 4881 MEs identi ed as appropriate for in- fore, although we have received suppliers’ ri ed. Approximately 21% of the collection clusion in the NPC Screening Resource Certi cates of Analysis each sample has

T I O N AL HUM AN G E M R S AR C H UT / (579 compounds) were not available from that are registered only by WHO INN and also been subjected to independent quality any vendor and therefore required custom USAN, or compounds listed on the U.S. control at the NCGC to ensure its correct synthesis, either by NCGC chemists or via tari schedule, only a small proportion identity and >90% purity through liquid : D . L E J A/ N A contract synthesis. As of this publication, are available commercially. Currently 928 chromatography-mass spectrometry (LC/

C R E DI T syntheses have been completed for 220 of (19%) of these compounds have been pro- MS). ree types of detectors are used for

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Table 3. Procurement status of NPC. and cellular phenotypes (Fig. 5). All screening is done using the NCGC’s quantitative Drug source In current collection Procurement/synthesis Total HTS paradigm (66), in which every drug is in process screened at six or more concentrations over FDA* 1635 182 1817 four to ve orders of magnitude in the pri- 66 UK/EU/Canada/Japan* 756 177 933 mary screen ( ). e percentage of NPC compounds with activity in the assays used Total Approved* 2391 359 2750 so far averages 4.2% [hits classi ed accord- Testing Only 928 3953 4881 ing to (66)], above the average rate of 1.8% Total 3319 4312 7631 in assays across the NCGC’s larger screening collection (principally the Molecular Li- *These counts include approved veterinary drugs. braries Small Molecule Repository), which is consistent with the notion that “bioactive” the analysis. e primary analytical tech- at a wavelength of 220 nm. UV detection chemical structures frequently have multi- nique for assessing compound identity is becomes important for samples that give a ple activities that might not be predictable a MS. Identi cation is based on the expected poor response to ELSD (65). priori. Importantly, the assays against which nominal mass being detected. e primary the NPC has been screened have a wide di- technique for assessing analytical purity of APPLICATIONS versity of formats and readouts, eliminating the LC eluate is an evaporative light scat- us far, compounds in the NPC Screen- the possibility that this high hit rate is the tering detection (ELSD); the secondary ing Resource have been screened against result of an assay platform artifact (67, 68). technique is ultraviolet (UV) absorbance more than 200 assays of targets, pathways, Although beyond the purview of this Per- on March 5, 2012 stm.sciencemag.org Downloaded from

Fig. 5. Activities of the NPC screened against approximately 200 assays of targets, pathways, and cellular phenotypes. The heat map, in which each row represents a drug and each column an assay, is colored by the drug activity observed (type of concentration response curve produced) so that activation is colored red, inhibition is blue, inactive is white, and missing data is gray. A darker shade of red or blue indicates more conclusive activity (signiﬁ cant concentration response). These data will be made publicly available through PubChem (27), with links provided on the NPC Infor- matics Resource browser (26).

www.ScienceTranslationalMedicine.org 27 April 2011 Vol 3 Issue 80 80ps16 9 PERSPECTIVE spective, the individual and aggregate assay us of their successes (and failures) using the ous pro ling to which the NPC will be sub- screening data generated by using the NPC Resource and to contribute their results to jected. All data generated by the NPC will be will be of great interest for repurposing and PubChem. Laboratory-based screening placed into the NCGC’s publically available chemical genomics and will be published of the NPC Screening Resource is done at relational browser (NPC browser v2.0.0) [for example, (69, 70)] and made publicly the NCGC via collaboration with any re- (26), which will allow relationships between available via the NPC Browser (26) and searcher who has a disease-relevant assay. targets, pathways, diseases, and drugs to be PubChem (27). e screening requirements for the NPC queried in a user-de ned fashion. Improve- e NPC is currently being used for three are much less demanding than a typical ments will be made regularly in data rich- principal purposes: (i) repurposing drugs HTS campaign given the small number of ness and analysis capabilities. for the treatment of RNDs; (ii) de ning compounds (3500 as compared to >350,000 the activities of known drugs for improved for a typical HTS); in our experience, the as- A NATIONAL COLLABORATIVE toxicological understanding, modeling, and says that produce results most directly ap- RESOURCE prediction; and (iii) de ning the character- plicable to clinical applications use primary e creation of the NPC as a de nitive in- istics of small-molecule compounds that patient cells. We encourage any researcher formatics and screening resource is an im- confer biological activity. to contact us with their interest. Given the portant milestone but is only the rst step Repurposing. Although many examples expense of building and maintaining the in its use for repurposing and chemical exist of successful repurposing, only re- NPC Screening Resource, we cannot send genomics. We hope that the enumeration cently has the concept of large-scale, even copies of the collection to collaborators of all drugs registered and/or approved for comprehensive, examination of the disease (100 screens can be performed at the NCGC human and veterinary use, and the creation applications of clinically used drugs been with the amount of compound required to of laboratory resource for their screening, considered (22, 23). In order to be maxi- send to one collaborator), but we routinely will allow e orts to turn to the more im- mally reliable and useful, the collection be- have collaborators bring their assays to the portant questions of the Resources’ scien- ing screened must be comprehensive, the NCGC, or send them to us, for collaborative ti c and medical applications. e NPC will screening paradigm must minimize false screening. A solicitation for development only achieve its potential as a community

positives and false negatives, con rmatory and screening of RND assays for repurpos- resource because the scienti c and medical on March 5, 2012 testing should be done, and the data should ing applications has been released by the problems to which it can be applied will re- be made publically available. e substantial TRND program recently (71). For those require the full breadth of target, pathway, and infrastructure and diverse disease expertise searchers who prefer to reproduce all or part disease expertise. e NPC is intended as a required for such an e ort has until now pre- of the NPC Screening Resource in their own collaborative instrument, and we encour- vented the implementation of comprehen- laboratories, information on suppliers of all age researchers to use the NPC interactively sive repurposing. e NPC, in the context of compounds can be found in table S4 and on via our Web site and screening projects. All the collaborative mission of the NCGC and our Web site (26). NCGC programs are partnerships, and the the NIH erapeutics for RNDs (TRND) Toxicology. Although unanticipated Center currently has over 200 collabora- stm.sciencemag.org program (71) makes this comprehensive ap- biological activities of known drugs might tions with investigators worldwide. proach to drug repurposing feasible, and the be therapeutically bene cial for repurpos- Having provided what to our knowledge enormous unmet medical need—over 6000 ing, those activities may also be responsible is a de nitive listing of drugs intended or RNDs currently have no treatment—makes for unanticipated toxicological e ects. Drug approved for human use, we hope that the it urgent. Such repurposing will not only toxicity is a major reason that new drug de- chemical genomics and drug development provide the possibility of rapid therapeutic velopment programs fail (72), and approved communities will use the NPC to realize advances but also will obviate the need for drugs are regularly removed from the mar- the full potential of these drugs for human new ME development, which is a long and ket because of adverse e ects; frequently, health, addressing the many devastating and Downloaded from expensive process. Ultimately, application of the mechanism by which the toxicity oc- untreatable diseases for which therapeutics the NPC to a large number of diseases will curs is not known. To improve the reliability are so urgently needed. help determine the proportion of human and mechanistic understanding of chemical diseases that are amelioratable by a drug in toxicity, the NPC will be screened across a SUPPORTING ONLINE MATERIAL the current pharmacopeia; this question has very broad range of pathways and cellular www.sciencetranslationalmedicine.org/cgi/content/ both theoretical and practical importance, phenotypes relevant to toxicity as part of the full/3/80/80ps16/DC1 informing questions of common disease Tox21 program, a collaboration between the Table S1. Drug counts by regulatory agency/authority. mechanisms and helping determine the NCGC, the National Toxicology Program, Table S2. Example mistakes found in data sources. scope of the problem of therapeutic devel- the U.S. Environmental Protection Agency, Table S3. Suppliers of known bioactive collections. opment of the thousands of diseases cur- and FDA (73). Table S4. List of compound suppliers. rently without treatment. Chemical genomics. Ultimately, im- REFERENCES AND NOTES Virtual screening of the NPC Informat- provements in the e ciency of drug devel- 1. J. A. DiMasi, H. G. Grabowski, The cost of biopharmaceu- ics Resource can be performed by any in- opment and application to disease will rely tical R&D: Is biotech diﬀ erent? Manage and Decis Econ vestigator worldwide with an internet con- on improved understanding, and therefore 28, 469–479 (2007). nection, and we encourage researchers to predictability, of the general principles by 2. N. Feasey, M. Wansbrough-Jones, D. C. W. Mabey, A. W. Solomon, Neglected tropical diseases. Br. Med. Bull. 93, do so. To enable the research community which small molecules interact with their 179–200 (2010). and build the knowledge base of drug ac- biological targets. is long-term goal will 3. ORDR, NIH Oﬃ ce of Rare Diseases Research. Available: tivities, we encourage researchers to inform be greatly advanced by the broad and rigor- http://rarediseases.info.nih.gov/.

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