mel reichman on pool shark’s cues for more efficient drug discovery

Download Mel Reichman on Pool Shark’s Cues for More Efficient Drug Discovery

Post on 08-Jul-2015

1.576 views

Category:

Education

1 download

Embed Size (px)

DESCRIPTION

Mel Reichman, senior investigator and director of the LIMR Chemical Genomics Center at the Lankenau Institute for Medical Research presents at the chemistry department at Drexel University on November 12, 2009.Modern drug discovery by high-throughput screening (HTS) begins with testing hundreds of thousands of compounds in biological assays. The confirmed hit rate for typical HTS is less than 0.5%; therefore, 99.5% of the costs of HTS are for generating null data. Orthogonal convolution of compound libraries (OCL) is 500% more efficient than present HTS practice. The OCL method combines 10 compounds per well. An advantage of this method is that each compound is represented twice in two separately arrayed pools. The potential for the approach to better enable academic centers of excellence to validate medicinally relevant biological targets is discussed.

TRANSCRIPT

  • Accelerating Exploration of Chemical and Biological Space for Academic Drug Discoveryreichmanm@mlhs.org. www.limr.org (see research ServicesLCGC)

  • Lankenau Institute for Medical Research (LIMR). Wynnewood, PAis an non-profit organization of ~22 independent faculty and other principal investigators who conduct basic and clinical research in cancer, diabetes, and cardiovascular disease. Founded in 1927.In medicine, hope springs from research

  • Summary Origins of NIH Roadmap Accelerate Lead Discovery 500% New Models for Pharma-Academia Discovery

  • American Academia: A Golden Goose of Innovation?

    $100 Billion$500 Billion Bayh-Dole Act 1980

    Sheet1

    All Respondents20032001% Change

    License Options Executed4995405823

    Gross Licensing Income$1.5 Billion1.1 Billion36

    Total Patents Filed139951126524

    New Patents Filed8346681223

    Patents Issued4,112372111

    Startups Formed432494-13

    Sheet2

    Sheet3

  • Strangling a Golden GooseThe COX-2 Story

  • The COX-2 Story: Timeline1992: Patent filed1992: Merck and Searle begin COX-2 program 1998: Celebrex approved, 6 months later Vioxx approved4/11/2000: U.S. Patent No. 6,048,850 (the '850 patent) issues (kitchen sink)4/12/2000:UR initiates suit against Searle (Pfizer)3/5/2003:UR looses up to Supreme CourtOctober, 2003: NIH Roadmap announced

  • Why UR LostBecause the inventors here simply failed to take the last critical step of actually isolating a compound, or even developing a process through which one of skill would be directly led to such a compound, this patent involves "little more than a research plan," the court concluded. (http://pub.bna.com/ptcj/006161.pdf).

    The University had claimed a method requiring, yet provided no written description of, a compound that could inhibit COX-2 and, therefore, the patent was invalid.

  • "We are the National Institutes of Health, not the National Institutes of Biology," Elias A. Zerhouni, M.D. says.

    "We need to reengineer how we apply our research to humans."

    (http://www.the-scientist.com/2004/2/16/44/1)

    New Roadmap for 21st Century Translational Research

  • Harbinger of Change

  • Proboscis for Probes?volume 5 number 7 JUly 2009 nature chemical biology

  • http://genome.gov/Pages/About/OD/ReportsPublications/AustinHHT060806.pdf

  • High Throughput Screening? >99.5% of the cost is to generate null dataHTS is binary; 0.5% hit rate, 99.5% inert rate Positive confirmation rates from HTS = ca. 30%-80%False negatives rate > 0No other bioassay field runs n = 1 assays Goal of HTS is to find the best leads faster500% faster; with 80% fewer resources?

  • Self Deconvoluting Compressed Libraries

    Pooled sample testing dates to WWIIUsed in developing economies for blood safety testingNAT pooling trials ongoing in US (HIV, HCV)

  • Important Product Usage and Safety InformationThe ABBOTT PRISM HIV O Plus test (Human Immunodeficiency Virus Types 1 and 2 (E. coli, B. megaterium, Recombinant) Antigen and Synthetic Peptide) can be used by laboratory professionals to screen individual donations of blood for antibodies to HIV-1 (anti-HIV-1) Groups M and O and /or antibodies to HIV-2 (anti-HIV-2). ABBOTT PRISM HIV O Plus can also be used as an aid in the diagnosis of HIV-1/HIV-2 infection. This assay has not been validated for use with pooled specimens and is not intended for use on cord blood specimens.

  • Hughes-Oliver, JM. Pooling experiments for blood screening and drug discovery. In: Screening Methods for Experimentation in Industry, Drug Discovery, and Genetics. Dean, Angela; Lewis, Susan (Eds.), 21-47. Springer 2006 Motlekar N, Diamond SL, Napper AD. Evaluation of an orthogonal pooling strategy for rapid high-throughput screening of proteases. Assay. Drug. Dev. Technol. (2008) 395-405.Ferrand S, Schmid A, Engeloch C, Glickman JF. Statistical evaluation of a self-deconvoluting matrix strategy for high-throughput screening of the CXCR3 receptor. Assay Drug. Dev. Technol. (2005) 395-405. Devlin, J.; Lian, A.; Trinh, L.; Polokoff, M.; Senator, D.; Zheng, W.; Kondracki, J.; Kretschmer, P.; Morser, J.; Lipson, S.; Spann, R.; Loughlin, J.; Dunn, K.; Morrissey, M. High capacity screening of pooled compounds: Identification of the active compound without re-assay of pool members. Drug DeV. Res. (1996) 80-85.Feng BY, Shoichet BK. Synergy and antagonism of promiscuous inhibition in multiple-compound mixtures. J. Med. Chem. (2006) 2151-4.Chung, T. Screen Compounds Singly: Why Muck It Up? J. Biomol. Screening (1998) 171-173.Konings DA, Wyatt JR, Ecker DJ, Freier SM. Strategies for Rapid Deconvolution of Combinatorial Libraries: Comparative Evaluation Using a Model System. J. Med. Chem. (1997) 4386-95.Snider, M. Screening of Compound Libraries: Consomme or Gumbo? J. Biomol. Screening (1998) 169-170.Oprea, TI. Chemoinformatics in Drug Discovery. In: Chemoinformatics in Drug Discovery Oprea, TI (Ed.) 25-42, Wiley 2005.Cummins, D. Pharmaceutical drug discovery: hunting the blockbuster drug. In: Screening Methods for Experimentation in Industry, Drug Discovery, and Genetics. Dean, Angela; Lewis, Susan (Eds.) 69-114. Springer 2006.Zhang JH, Wu X, Sills MA. Probing the primary screening efficiency by multiple replicate testing: a quantitative analysis of hit confirmation and false screening results of a biochemical assay. J. Biomol. Screen. (2005) 695-704. Hann, M., Hudson, B., Lewell, X., Lifely, R., Miller, L., Ramsden, N. Strategic Pooling of Compounds for High-Throughput Screening. J. Chem. Inf. Comput. Sci. 1999, 39, 897-902.von Ahsen O, Schmidt A, Klotz M, Parczyk K. Assay concordance between SPA and TR-FRET in high-throughput screening. J Biomol Screen. (2006) 606-Leach AR, Bradshaw J, Green DV, Hann MM, Delany JJ 3rd. Implementation of a system for reagent selection and library enumeration, profiling, and design. J. Chem. Inf. Comput. Sci. (1999) 1161-72.Spencer R. W. High-throughput screening of historic collections: observations on file size, biological targets, and file diversity. Biotechnol. Bioeng. (1998) 61-67. 1Relevant References Suggest Productive Paths Forward

  • New Approaches, Software and Data Mining

    www.ceuticalsoft.com

  • The retinoblastoma tumor suppressor pathway contains multiple oncogenes (green) and tumor suppressors (red) and is dysfunctional in almost every human tumorMnger K PNAS 2003;100:2165-2167

  • ELISA assay was adapted to 384-well format to do a HTS of >80,000 compoundsAssay measures the amount of E2F bound to pRb upon addition of 16E7 (CR2/CR3) +/- compoundprevent E7-mediated E2F displacement from pRb Kindly provided by D. Ferra, Wistar Institute)

  • Pilot Run Library OCL009 9 E7-inhibitorspRB/E2F

    Exp Data Matrix

    Experiment Data Assay Plate 1

    123456789101112131415161718192021222324

    A0.8839736623-0.0549766669-0.2288563575-0.0795243879-0.2309020009-0.1654414115-0.16339576810.0432142172-0.2534040785-0.3229559547-0.216582497-0.1081633958-0.0570223103-0.0406571629-0.0774787445-0.2329476443-0.03656587610.0800357988-0.1818065588-0.1368024036-0.1347567602-0.0672505274-0.03247458930.9617081123

    B0.92897781760.1639071789-0.0815700313-0.0999808221-0.3209103113-0.0877069616-0.177715272-0.0877069616-0.18589784570.0350316435-0.2452215048-0.2206737838-0.2288563575-0.1306654734-0.265677939-0.1306654734-0.0242920156-0.2247650706-0.0570223103-0.1920347759-0.12452854310.0493511475-0.04883973660.9985296938

    C1.0169404846-0.0242920156-0.0467940932-0.241130218-0.1224828997-0.2309020009-0.0754331011-0.0938438918-0.1961260628-0.2063542799-0.0345202327-0.2227194272-0.2554497219-0.2779517995-0.0917982484-0.1633957681-0.0774787445-0.089752605-0.153167551-0.21249121010.0002557054-0.05702231030.0227577831.0742185003

    D1.07421850030.0023013488-0.15930448120.5484881417-0.3127277376-0.065204884-0.12861983-0.2963625903-0.304545164-0.2145368535-0.265677939-0.15930448120.0063926357-0.0202007288-0.2083999233-0.1183916129-0.1756696286-0.0590679537-0.1204372563-0.0304289459-0.0611135971-0.1122546826-0.04679409320.9351147478

    E0.9698906859-0.0611135971-0.0836156747-0.3250015982-0.1306654734-0.1593044812-0.0979351787-0.1920347759-0.2595410088-0.2083999233-0.1736239852-0.1613501247-0.0979351787-0.2288563575-0.0181550853-0.177715272-0.0774787445-0.304545164-0.2145368535-0.14498497730.18231796970.00230134880.04935114750.9146583136

    F0.92284088730.2314134117-0.16339576810.0513967909-0.1306654734-0.0692961708-0.2124912101-0.3229559547-0.0324745893-0.0795243879-0.2759061561-0.1224828997-0.1490762641-0.09179824840.02684906990.0943553027-0.1020264655-0.3331841718-0.01201815510.0166208528-0.04883973660.10662916320.00434699231.0885380042

    G1.07830978710.01866649620.0820814422-0.13271111680.0063926357-0.026337659-0.1040721089-0.1899891325-0.0365658761-0.1368024036-0.0815700313-0.0958895353-0.0979351787-0.16953269830.0964009461-0.0979351787-0.0795243879-0.1572588378-0.0386115195-0.1020264655-0.128619830.03298600010.08003579881.0026209806

    H1.0005753372-0.0938438918-0.3229559547-0.2206737838-0.1122546826-0.2595410088-0.1572588378-0.0324745893-0.13475676020.4482516141-0.2063542799-0.2472671482-0.1695326983-0.02429201560.0943553027-0.241130218-0.0304289459-0.2963625903-0.0815700313-0.1593044812-0.0590679537-0.0549766669-0.12452854310.9637537557

    I1.1253595858-0.0795243879-0.1102090392-0.0795243879-0.1408936905-0.3597775363-0.0815700313-0.10611775230.0104839225-0.0815700313-0.0283833024-0.114300326-0.2043086365-0.1736239852-0.001789938-0.1470306207-0.1838522023-0.3904621876-0.0242920156-0.1552131944-0.0447484498-0.09179824840.02071213960.9003388097

    J1.1110400818-0.0611135971-0.08361567470.0023013488-0.1163459694-0.1490762641-0.0386115195-0.01406379850.0759445119-0.0202007288-0