Finding promiscuous old drugs for new uses

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In the last 6 years high-throughput screening has been used to identify FDA approved drugs that are active against multiple targets (also termed promiscuity). We have identified 34 studies that have screened libraries of FDA approved drugs against various whole cell or target assays. Each study has identified one or more compound with a new bioactivity that had not been previously described. Thirteen of these drugs were active against more than one additional disease, thereby suggesting a degree of promiscuity. The 109 molecules identified by screening in vitro were statistically more hydrophobic than orphan designated products with at least one marketing approval for a common disease indication or one marketing approval for a rare disease (FDA rare disease research database). We have created a database of in vitro data on old drugs for new uses that could be applied for repositioning these or other molecules for neglected and rare diseases.

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  • CDD Experienced Team Innovates and Executes Barry Bunin, PhD (Pres. & Cofounder as first Eli Lilly EIR) Libraria (CEO, Pres.-CSO), Arris Pharmaceuticals (Sr. Scientist), Genentech, UC Berkeley (Ellman), Columbia University, author. Moses Hohman, PhD (Director Software Engineering) Northwestern Assoc. Director of Bioinformatics, Thoughtworks, Inc., U of Chicago (PhD), Harvard ( magna cum laude, Physics) Sylvia Ernst, PhD (Director Community Growth & Sales) Left 800-lb Gorillas: Accelrys-Scitegic, MDL-Elsevier-Beilstein Peter Cohan (BOD & Overall Sales Strategy) Symyx (VP Bus Dev & President-Discovery Tools), MDL (VP Customer Marketing), www.secondderivative.com, author. Omidyar Network, Founders Fund, & Lilly (BOD observers) WSGR (Corporate Counsel), Rina Accountancy (GAAP compliance) Partners: Hub Consortium Members, ChemAxon, DNDi, MMV, Sandler Center… CDD SAB: Christopher Lipinski PhD, James McKerrow, MD PhD, David Roos PhD, Adam Renslo PhD, Wes Van Voorhis, MD PhD
  • Finding promiscuous old drugs for new uses

    1. 1. Finding Promiscuous Old Drugs for New Uses Sean Ekins1,2,3,4 and Antony J. Williams5 1 Collaborations in Chemistry, Fuquay Varina, NC. 2 Collaborative Drug Discovery, Burlingame, CA.3 Department of Pharmacology, University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ. 4 School of Pharmacy, Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD. 5 Royal Society of Chemistry, Wake Forest, NC
    2. 2. Why old drugs ?  More cost effective R&D?  Repurposing/ repositioning -Quicker to bring to market?  Recent focus on neglected & rare diseases  Over 7000 diseases affecting less than 200,000  1000’s of diseases with no treatments  >300 orphan drugs approved since 1983Ekins S, Williams AJ, Krasowski MD and Freundlich JS, Drug Disc Today, 16: 298-310, 2011
    3. 3. Just some of the many rare disease groupsAbigail Alliance for Better Access to Developmental Drugs MPD SupportAddi & Cassi Fund National Gaucher FoundationAmerican Behcets Disease Association National MPS SocietyAmschwand Sarcoma Cancer Foundation National Organization Against Rare CancersBDSRA (Batten Disease Support and Research Association) National PKU AllianceBeyond Batten Disease Foundation National Tay-Sachs & Allied Diseases AssociationBlake’s Purpose Foundation New Hope Research FoundationBreakthrough Cancer Coalition NextGEN PolicyCanadian PKU & Allied Disorders Noahs Hope - Batten disease research fundCenter for Orphan Disease Research and Therapy, University of Our Promise to Nicholas FoundationPennsylvania Oxalosis and Hyperoxaluria FoundationChildren’s Cardiomyopathy Foundation Partnership for CuresCooleys Anemia Foundation Periodic Paralysis AssociationDani’s Foundation RARE Project Ryan Foundation for MPS ChildrenDrew’s Hope Research Foundation Sanfilippo Foundation for ChildrenEveryLife Foundation for Rare Diseases Sarcoma Foundation of AmericaGIST Cancer Awareness Foundation Solving Kids CancerHannahs Hope Fund Taylors Tale: Fighting Batten DiseaseHope4Bridget Foundation Team Sanfilippo FoundationHypertrophic Cardiomyopathy Association - HCMA The Alliance Against Alveolar Soft Part SarcomaI Have IIH The Life Raft GroupISRMD (International Society for Mannosidosis and Related Diseases) The NOMID AllianceJacob’s Cure The Transverse Myelitis AssociationJain Foundation The XLH Network, Inc.Jonahs Just Begun-Foundation to Cure Sanfilippo Inc. United Pompe FoundationKids V CancerKurt+Peter FoundationLGMD2I Research FundLymphangiomatosis & Gorhams Disease AllianceMAGIC Foundation Many of these groups areManton Center for Orphan Disease ResearchMarbleRoad doing R&D on a shoestring howMary Paytons Miracle FoundationMidwest Asian Health Association (MAHA) can we help?
    4. 4. One example of why Pharmaceutical R&D needs disruptingJonah has Sanfilippo Syndrome – Mucopolysaccharidosis type III – cannot degrade heparansulfate - NeurodegenerationJonah’s mum, Jill Wood started a foundation, raises money, awareness, funds ground breakingresearch happening globally. Willing to sell her house to fund research to save Jonah.She is in a race against time – what can we do to translate ideas from bench to patient faster?How do we get more ideas tested, can we focus on approved drugs?How can we help parents and families ?
    5. 5. Availability of libraries of FDA drugsJohns Hopkins Clinical Compound library- made compounds available at cost
    6. 6. Finding Promiscuous Old Drugs for New Uses  In late 2010..searched the literature  Many groups in vitro HTS  Libraries of FDA approved drugs against various whole cell or target assays  Research published in the prior six years - 34 studies -.  1 or more compounds with a suggested new bioactivity  13 drugs were active against more than one additional disease in vitro  Perhaps screen these first?Ekins and Williams, Pharm Res 28(8):1785-91, 2011
    7. 7. Finding Promiscuous Old Drugs for New Uses Multiple tricyclicsEkins and Williams, Pharm Res 28(8):1785-91, 2011
    8. 8. Finding Promiscuous Old Drugs for New Uses  Amitriptyline and clomipramine = suppress glial fibrially acidic protein  Cho et al., Human Mol Genet (2010) 19: 3169-78  Amitriptyline and clomipramine = mitochondrial permeability transition  Stavrovskaya et al., J Exp Med (2004) 200: 211-22  Pyrvinium Pamoate (antihelmintic) = anti Tuberculosis  Lougheed et al., Tuberculosis (2009) 89: 364-70  Pyrvinium Pamoate (antihelmintic) = anti Antiprotozoal C. parvum  Downey et al., Antimicrob Agents Chemother (2008) 52: 3106-12  Pyrvinium Pamoate (antihelmintic) = anti Antiprotozoal T. Brucei  Mackey et al., Chem Biol Drug Des (2006) 355-63Ekins and Williams, Pharm Res 28(8):1785-91, 2011
    9. 9. Analysis of datasets Dataset ALogP Molecular Number Number Number Number of Number Molecular Weight of of Rings of Hydrogen of Polar Rotatable Aromatic bond Hydrogen Surface Area Bonds Rings Acceptors bond Donors Compounds 3.1 ± 428.4 ± 202.8 5.4 ± 3.8 3.8 ± 1.9 2.0 ± 1.4 5.6 ± 4.2 2.0 ± 1.9 89.6 ± 69.3identified in vitro with 2.6 new activities (N = 109) * Compounds 3.6 ± 442.8 ± 150.0 5.1 ± 3.1 4.2 ± 1.5 1.8 ± 1.2 5.5 ± 4.6 2.2 ± 3.3 79.5 ± 78.8identified in vitro with 2.7 multiple new activities (N = 13) •Promiscuous repurposed compounds are more hydrophobic, •orphan repurposed hits are less hydrophobicEkins and Williams, Pharm Res 28(8):1785-91, 2011
    10. 10. Finding Promiscuous Old Drugs for New Uses 109 molecules were identified by screening in vitro Promiscuous compounds do not appear different to whole dataset Molecules are close to natural product lead like (MW<460, LogP <4.2) Rosen et al., J Med Chem (2009) 52: 1953-62 1193 Oral drugs mean MW 343.7 CLOGP 2.3 Vieth et al., J Med Chem (2004) 47: 224-32 Others have shown GPCR promiscuous cpds vs selective have higher MW and clogP Azzaoui et al., ChemMedComm (2007) 2: 874-80 Our promiscuous cpds had carbon skeletons identified as promiscuous
    11. 11. FDA Rare Disease Research Database• The FDA resource, the rare disease research database (RDRD),(http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesignation/ucm216147.htm)• Lists Orphan-designated products with at least one marketing approval for acommon disease indication, for a rare disease indication, or for both common andrare disease indications.• In the last category there are less than 50 molecules (including largebiopharmaceutical drugs).• These tables do not capture the high throughput screening (HTS) data generated todate•FDA databases for rare disease research are XL files!!
    12. 12. New datasets We have curated the data and uploaded in CDD with the help of Antony Williams at the Royal Society of Chemistry© 2009 Collaborative Drug Discovery, Inc. Archive, Mine, Collaborate
    13. 13. Analysis of datasets Dataset ALogP Molecular Number Number Number Number of Number Molecular Weight of of Rings of Hydrogen of Polar Rotatable Aromatic bond Hydrogen Surface Area Bonds Rings Acceptors bond DonorsOrphan designated 1.4 ± 353.2 ± 218.8 5.3 ± 6.4 2.8 ± 1.7 1.2 ± 1.3 5.3 ± 6.0 2.5 ± 3.0 99.2 ± 110.7 products with at 3.0 b a a bleast one marketing approval for a common diseaseindication (N = 79) # Orphan designated 0.9 ± 344.4 ± 233.5 5.3 ± 5.3 2.4 ± 1.9 1.3 ± 1.4 6.2 ± 4.2 2.7 ± 2.8 114.2 ± 85.3 products with at 3.3 b a b aleast one marketing approval for a raredisease indication (N = 52) # orphan repurposed hits are less hydrophobic smaller MW than in vitro screening cpds Molecules close to lead-like and closer to oral drugsEkins and Williams, Pharm Res 28(8):1785-91, 2011
    14. 14. Dataset Intersection Orphan + Common Orphan + Use 0 Rare use 0 3 5 In vitro hitsDo these represent frequentactives or promiscuouscompounds?
    15. 15. Finding Promiscuous Old Drugs for New Uses In vitro screening compounds repurposed – Statistically more hydrophobic (log P) and higher MWT than orphan- designated products with at least one marketing approval for a common disease indication or one marketing approval for a rare disease from the FDA’s rare disease research database. Created multiple structure searchable databases in CDD Data for repurposing in publications is increasing but who is tracking it? Limited follow up of compounds from in vitro to in vivo.. Will any of these compounds from in vitro be approved? Then the NPC browser was released early 2011
    16. 16. Government Databases Should Come With a Health Warning Openness Can Bring Serious Quality IssuesDatabase released and within days 100’s of errors found in structures Science Translational Medicine 2011 NPC Browser http://tripod.nih.gov/npc/ Science Translational Medicine 2011 Williams and Ekins, DDT, 16: 747-750 (2011)
    17. 17. Data Errors in the NPC Browser: Analysis of Steroids Substructure # of # of No Incomplete Complete but Hits Correct stereochemistry Stereochemistry incorrect Hits stereochemistryGonane 34 5 8 21 0Gon-4-ene 55 12 3 33 7Gon-1,4-diene 60 17 10 23 10
    18. 18. Why drug structure quality is important? More groups doing in silico repositioning Target-based or ligand-based Network and systems biology They are all integrating or using sets of FDA drugs..if the structures are incorrect predictions will be too.. What is need is a definitive set of FDA approved drugs with correct structures and tools for in silico screening Also linkage between in vitro data & clinical data
    19. 19. Repurpose FDA drugs in silico Key databases of structures and 2D Similarity search with “hit” bioactivity data FDA drugs from screening database Export database and Suggest use for 3D searching approved with a pharmacophore drugs for testing or other model - may also indicate other uses if it is present in more than one database Suggest in silico hits for in vitro screeningEkins S, Williams AJ, Krasowski MD and Freundlich JS, Drug Disc Today, 16: 298-310, 2011
    20. 20. An example for TB and more  Bayesian models for TB whole cell data  200,000 single point % hits identified  Over 2000 dose response  Used publication that identified compounds with whole cell activity FDA drugs 2108 molecules (21 actives)  Lougheed et al., Tuberculosis (2009) 89:364-70  Numerous examples of pharmacophores screening drugs and finding transporter inhibitors, PXR agonists, PXR antagonists etc.. Ekins et al., Mol Pharmacol, 74(3):662-72 , (2008)  Could use large datasets for other diseases, targets to build models search FDA drugs….and repurposeEkins et al., Mol BioSyst, 6: 840-851, 2010 Ekins and Freundlich, Pharm Res, 28, 1859-1869, 2011.
    21. 21. Need to learn from neglected disease research Do we really need to screen massive libraries of compounds as we have for TB and malaria? And groups are screening compounds already screened by others! Ekins S and Williams AJ, MedChemComm,http://www.slideshare.net/ekinssean 1: 325-330, 2010.
    22. 22. Rare diseases: Searching for Potential Chaperonesfor Sanfilippo Syndrome  Pshezhetsky et al showed Glucosamine rescues HGSNAT mutants  Feldhammer et al., Hum Mutat. 2009 30:918-25  Glucosamine used to create a 3D common features pharmacophore using Discovery Studio.  The pharmacophore + ligand van der Waals shape was used to search multiple 3D databases  FDA drugs, natural products, orphan drugs, KEGG, CSF metabolome etc.  The pharmacophore consists of a positive ionizable (red) and 3 hydrogen bond donor groups (purple).  Selected hits for experimental testing  Collaboration ongoing! e.g. Isofagomine maps pharmacophore
    23. 23. A path forwards for rare diseases using old drugs?We propose generalizable methods utilizing transcriptomic, system-wide chemical biologydatasets combined with chemical informatics and, where possible, repurposing of FDAapproved drugs for pre-clinical orphan disease therapies.A generalizable pre-clinical research approach for orphan diseasetherapy Chandree L. Beaulieu et al., submitted 2012
    24. 24. Crowdsourcing Project “Off the Shelf R&D” How can we access more chemistry space? All pharmas have assets on shelf that reached clinic “Off the Shelf R&D” Get the crowd to help in repurposing / repositioning these assets How can software help? - Create communities to test - Provide informatics tools that are accessible to the crowd - enlarge user base - Data storage on cloud – integration with public data - Crowd becomes virtual pharma-CROs and the “customer” for enabling services
    25. 25. Finding Promiscuous Old Drugs for New Uses Update 2011-2012 everolimus 5-fluorouracil ceftriaxoneCould In silico / in vitro repositioning find leads-drugs quicker?
    26. 26. Acknowledgments Jill Wood Joel Freundlich (UMDNJ), Matthew D. Krasowski (University of Iowa) Chris Lipinski David Sullivan (Johns Hopkins) Accelrys CDD – Barry Bunin Everyone that has shared data in CDD.. Email: ekinssean@yahoo.com Slideshare: http://www.slideshare.net/ekinssean Twitter: collabchem Blog: http://www.collabchem.com/ Website: http://www.collaborations.com/CHEMISTRY.HTM

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