Presentation of Evolution of Compound Management Systems in an Academic Environment

1. Evolution of Compound Management Systems in an Academic Environment Gregory J. Wendel, Ph.D. The Siegel Consulting Group, Inc December 7, 2010

4. Broad Platforms The Broad's Scientific platforms are made up of professional scientists with the expertise and organization to carry out major projects that cannot be done within a single laboratory Broad Programs The Broad's Scientific programs bring together research groups with a shared commitment to important biomedical challenges Broad Faculty 6 Core Members in Broad buildings 155 Associate Members: faculty with labs at MIT, Harvard, Whitehead, or affiliated hospitals Imaging RNAi Chemical Biology/Novel Therapeutics Proteomics Genetic Analysis Genome Sequencing Biological Samples A unique collaborative structure enables the Broad mission Computational Biology Infectious Disease Chemical Biology Medical & Popul’n Genetics Psychiatric Disease Stanley Center Metabolic Disease Cell Circuits Genome Biology Cancer

5. The Broad Institute Chemical Biology Platform 1998 2011 2004 2008 Screening at Institute of Chemistry and Cellular Biology (ICCB), Harvard Medical School; Early DOS concepts Broad Institute of Harvard & MIT Automation online; MLPCN comprehensive screening center (BIPDeC); 1 st platform DOS compounds 2007 Automated screening system design (HighRes Biosolutions) 2006 Platform DOS library design 2009 The Broad Institute, Inc. 200k platform DOS compounds online 2002 NCI Initiative for Chemical Genetics

10. Compound Registration Process – 2008-2009 Jira Chemist submits Compound (s) Compound in vial Verify contents, Export SDF Review for issues SDF Normalization Normalized Structure Curated Structure BRD, data Curate Structures Excel file w/ structure, supplier, etc Sample ID Created BRD Created CBIP Pipeline Pilot Human Time Line 1.7 Man-Hour (Registration) 10 Day duration (Avg) Transfer to vial and weigh

12. Change in the Scope of the Screening Center NCI Initiative for Chemical Genetics NIH MLPCN Comprehensive Screening Center Extensive Collaboration with Academia Extensive Collaboration with Academia 12 Primary Screens per year 25 Probe Projects per year Walk-up Instrumentation Walk-up & Integrated Automation Primary Screen & Limited Dose Response Dose Response & Secondary Assays ChemBank PubChem Commercial + small-scale internal libraries NIH MLSMR, commercial, legacy, + production-scale internal libraries No routine internal compound QC 100% QC (>75% LC/MS UV 210 )

17. Summary of Compound QC (DOS + Legacy) Collection Total number of compounds Total number of compounds passing QC (>75% purity by UV 210 ) Legacy 56,162 42,794 (76.2%) DOS 63,069 52,819 (83.7%) New commercial 4,931 4,846 (98.3%) Pending DOS 16,804 TBD Pending commercial 17,779 TBD Total completed 124,162 100,459 (80.9%)

21. Automation Integration In collaboration with HighRes BioSolutions ~2400 sq. ft Long-term compound store Compound management module General screening module BL2 mammalian screening module BL2 bacteria/yeast screening module

22. Long-term Compound Storage System Nexus Universal Labstore AI Module for tube delivery Tube Selector IO Station HighRes MicroDock Staubli Robotic Arm Cellario PC

24. Compound Management System BL2 BL2+ General Screening Photo credit: HighRes BioSolutions

29. Revised Compound Registration Process Time Line 1.7 Man-Hour (Registration) 10 Day duration (Avg) Chemist submits Compound(s) Compound in vial Verify contents, Export SDF Review for issues SDF Normalization Normalized Structure Curated Structure BRD, data Curate Structures Excel file w/ structure, supplier, etc Sample ID Created BRD Created CBIP Pipeline Pilot Human Transfer to vial and weigh Chemist has Compound(s) Register via ELN Submit vials to CM Time Line 0.5 Man-Hour (Registration) 0.5 Hour duration (Avg)

35. Broad Chemical Biology: DOS Synthesize diverse small molecules having structural complexity rivaling naturally occurring small molecules, and having chemical handles that enable systematic optimization or modification (e.g., for making target I.D. reagents, or for adding biasing elements). Process Chemistry Robust and practical synthesis of scaffolds Medicinal Chemistry Built-in SAR Handles for Target ID Structural Diversity Emphasis on stereochemical and skeletal diversity

37. A Build/Couple/Pair (B/C/P) strategy for DOS Nielsen T.E.; Schreiber, S.L. Angew. Chem. Int. Ed . 2008 , 47 ,48-56

38. 2008: New Compound Collection

39. Chemical Biology screening collection Broad (~102K) MLPCN (~324K) MLPCN Library Properties: Purity > 90% (vendor specified) Availability (10 mg) and re-supply (20 mg) MW ≤ 600 CLogP ≤ 6 Calculated solubility ≥ 20 ug/mL MW vs ALogP Molecular Weight ALogP CVL DOS STRD NATP Code Collection name # of compounds CBLI DOS 61,004 CHRM Chromatin biased 2,327 BIOA Bioactives 4,920 STRD Non-commercial stereochemically diverse 2,115 NATP Natural products - purified 1,291 KINA Kinase biased 12,119 COMA Commercial - Forma 1,133 COMB Commercial - other 12,278 GPCR G protein-coupled receptor biased 5,000 102,187 New code Collection name # of compounds COMB Commercially available 296,780 BIOA Bioactives 442 STRD Non-commercial stereochemically diverse 14,801 NATP Natural products - purified 1,472 GPCR G protein-coupled receptor biased 3,880 IONC Ion channel targeted 1,956 KINA Kinase biased 3,892 NUCR Nuclear receptor targeted 152 PROT Protease targeted 684 324,059

43. Acknowlwdgements Lisa Marcaurelle DOS Chemistry Michelle Palmer Josh Bittker Screening Mike Foley Stuart Schreiber Aly Shamji Edward Scolnick Informatics Andrea De Souza Raza Shaikh Paul Clemons Computational Research The Broad Institute – Chemical Biology Platform http://www.broadinstitute.org/scientific-community/science/platforms/chemical-biology Compound Management Sean Collignon Corrie Lade John McGrath HighRes BioSolutions http://www.highresbio.com/ Lou Guarrancina Michael Nichols Vlad Zhirnov Ira Hoffman John Smyka Scott Rehlander Siegel Consulting Group http://www.siegelcg.com Gregory Wendel