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A ‘Broad’ View of Translational Research at the Stanley Center
CDD Community MeetingJanice Kranz, Assistant Director of Stanley Center
for Psychiatric Research at the Broad InstituteOct. 7, 2008
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Outline
Introduction• Broad Institute• Stanley Center for Psychiatric Research• ‘Genomics to Medicine’
Examples with CDD• Compound Registration System• Mining IC50 Data for Target Selectivity
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Broad Institute mission
Bring the power of genomics to biology and medicine
The Broad Institute is a research collaboration of MIT, Harvard and its affiliated hospitals, and the Whitehead Institute.
More specifically:Empower creative scientists to:• Construct new powerful tools for genomic medicine,• Make them accessible to the global scientific community, and •Apply them to the understanding and treatment of disease.
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Broad PlatformsThe 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 ProgramsThe Broad's Scientific programs bring together research groups with a shared commitment to important biomedical challenges.
Novel Therapeutics
Imaging
RNAi
Chemical Biology
Proteomics
Genetic Analysis
Genome Sequencing
Biological Samples
A unique collaborative structure enables the Broad mission
Broad Faculty6 Core Members in Broad buildings
108 Associate Members: faculty with labs at MIT, Harvard, Whitehead, or affiliated hospitals
Computational Biology
Infectious Disease
Chemical Biology
Medical & Popul’nGenetics
Psychiatric Disease
Metabolic Disease
Cell Circuits
Genome Biology
Cancer
*
**
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Funded by Ted and Vada Stanley through the Stanley Medical Research Institute
MissionTo discover the human genes that confer risk for bipolar disorder and schizophrenia and to use this information to develop new diagnostic tests and treatments for these illnesses.
HistoryGrew from Psychiatric Disease Initiative (now ‘Program’)
Founding members of Psychiatric Disease Initiative (2005): Ed Scolnick Pamela Sklar Stephen Haggarty
Stanley Center for Psychiatric Research
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HumanGenetics
Neurobiology
ChemicalBiology
Bipolar Disorder
Schizophrenia
Approaches
Dis
ease
s
Major Depression
Stanley Center for Psychiatric Research
• New approaches to discover potentially different biology and leads for therapeutic development• No assumption about genetic architecture
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International Schizophrenia Genetics Consortium
Pamela Sklar
Hugh GurlingAndrew McQuillin
Michael OwenMichael O’Donovan
Douglas BlackwoodDavid PorteousWalter Muir
Edward ScolnickPamela Sklar
David St. Clair
Michael GillAiden Corvin
Carlos PatoMichele Pato
Paul LichtensteinChristina Hultman
Patrick F. Sullivan
QuickTime™ and aUncompressed) decomneeded to see this pict
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International Case-Control Cohort for Bipolar Disorder
Nick Craddock
Christina HultmanMikael Landen
Carlos Pato
Jordan Smoller
Goal: 10,000 cases and controls in ~2 or so yearsFunded by the NIMH and an additional grant from the Stanley Medical Research Institute
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Genome-Wide Association Studies (GWAS): Examples
Published online July 30 ‘08
Published online August ‘08
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Follow-up Biology needed to take GWAS Results to ChemBioFor Schizophrenia• Explore role of major deletions—which gene(s) are involved?• Look for measurable effect on biology--cell lines from patients for
protein, mRNA differences; • SNP analysis also revealing individual genes-same follow-up as in
BPFor Bipolar Disorder:• ANK3 and CACNA1C suggest BP may be ‘ion channelopathy’• Pathway analysis to identify ‘best’ targets• Nature of defect (alt. splicing, altered activity, loss-of-function…)• Determine whether agonist or antagonist needed• Develop assays• Test in vivo with RNAi• Explore use of existing
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CholesterolObesityMyocardial infarctionQT intervalAtrial FibrilliationType 2 DiabetesProstate cancerBreast cancerColon cancer
KCNJ11
20032000
PPARγ
2001
IBD5NOD2
2005 20062002
CTLA4
2004
PTPN22
Age-Related Macular DegenerationCrohn’s DiseaseType 1 DiabetesSystemic Lupus ErythematosusAsthmaRestless leg syndromeGallstone diseaseMultiple sclerosisRheumatoid arthritisGlaucoma
CD25IRF5
PCSK9CFH
NOS1APIFIH1
PCSK9CFB/C2
LOC3877158q24IL23R
TCF7L2
2007
CDKN2B/A8q24 #28q24 #38q24 #48q24 #58q24 #6ATG16L15p1310q21IRGMNKX2-3IL12B3p211q24PTPN2TCF2CDKN2B/AIGF2BP2CDKAL1
FGFR2TNRC9MAP3K1LSP18q24LOXL1IL7RTRAF1/C5STAT4ABCG8GALNT2PSRC1NCANTBL2TRIB1KCTD10ANGLPT3GRIN3A
HHEXSLC30A8MEIS1LBXCOR1BTBD9C38q24ORMDL34q25TCF2GCKRFTOC12orf30ERBB3KIAA0350CD22616p13PTPN2SH2B3
GWAS: Progress In The Identification OfGene Variants For Common Diseases
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Common Variants in Established Drug Targets Identified by GWAS
Frayling, Nature Reviews Genetics’07; 8:657
odds ratio 1.14 per allele95% CI (1.10-1.19)
5x10-1135%E23Krs215Sulfon-ylureas
Type 2 diabetesKCNJ11
Diabetes Genetics Initiative, Science ’07; 316:1341
odds ratio 1.14 per allele95% CI (1.08-1.20)
2x10-687%P12Ars1801282
thiazolidinediones
Type 2 diabetesPPARG
Kathiresan, Nature Genetics’08; 40:189
4 mg/dLdifference in LDL cholesterol between homozygote classes
1x10-2039%A/Trs12654264StatinsLDL
cholesterolHMGCR
ReferenceEffect sizeStatistical evidence (p-value)
Allele freq-uency
AlleleSNP*(rsnumber)
DrugTrait or Disease
Gene Name
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Lesson from HMGCR on Genetic Variation vs. Potential Therapeutic Effect
The frequency and effect size (4 mg/dL) of genetic variation bears no clear relationship to therapeutic impact of mechanism-driven intervention (>40 mg/dL)
Evolution vs. Therapy:Alleles are limited by natural selection,
developmental biology, and pleiotropy
Drugs aimed at the same pathway are not necessarily limited in the same way
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HumanGenetics
Neurobiology
ChemicalChemicalBiologyBiology
Bipolar Disorder
Schizophrenia
Approaches
Dis
ease
s
Major Depression
Stanley Center for Psychiatric Research
• New approaches to discover potentially different biology and leads for therapeutic development• No assumption about genetic architecture
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Laboratory Operations
MGHCHGR
MITBroad
Chemical Neurobiology Laboratory of the Stanley Center: Haggarty Lab
Assay Development +Follow-up Neurobiology
High-Throughput Screening, Chemistry + Target ID
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Synthetic ChemistryComputational Chemistry
Medicinal Chemistry
BiologyChemicalScreens
Follow-upFrom Screens
Medicine
Genetics
Broad Novel Therapeutics
+ Optimization(ADME-PK, Tox)
Core Drug Design Team
• assay dev.• access to cpds
• multiple assays• behavior (in vivo)
hit lead
• outsourced animals• outsourced chem.
Dr. Mike MoyerDr. Mike FoleyDr. Robert Gould
Chemical Neurobiology Laboratory: Chemistry Activities
Project #1: Cognitive Disorders(HDAC/chromatin remodeling)
Project #2: Bipolar Disorder(lithium/valproate pathways)
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Reversible Changes in Chromatin Structure Control Gene Expression in the Brain
Tsankova et al. (2007) Nat. Neuro.
CBP
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de Ruijter et al. (2003) Biochem J.
catalytic domainNLS
Key Role for Histone Acetylation: HDACs
HAT HDAC
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Evidence from the literature: HDAC inhibitors are beneficial for learning + memory in mice
- CBP+/- (HAT) or CBPDN+/- mice display impaired LTP and learning.
The impairment can be ameliorated by administration of HDAC inhibitors Alarcon et al., 2004 Neuron; Korzus et al., 2004 Neuron
- Non-selective HDAC inhibitors increased histone H3 and H4 acetylation, facilitated spatial and associative learning and synaptic plasticity in WT mice Levenson et al., 2004 JBC
- Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcription activation Vecsey et al., 2007 J Neurosci
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Goal: Isoform-specific HDAC Inhibitors with Desired Activities in Multiple Secondary Assays
Neurobiology and behavior suggest different HDACs are targets for learning/memory vs. mania/ depressionScreening Plan:
• Enzymatic--end point and kinetic; panel of Class I and II HDACs• Cell-based Assays
• Cell lines: reporter genes to monitor desired specific gene or protein expression
• Primary neuronal cultures to measure reporter gene activity and/or measure in vivo histone acetylation
• ADME/PK of desired compounds• In Vivo
• Behavior (multiple paradigms)• Follow-up assay of brain regions for histone acetylation/ other phenotypes
Ideally, all assay data stored in, and mined from, a DB
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Our Challenge: Research and Med ChemProgress ‘ahead’ of Broad’s ChemBio Informatics
Broad ChemBio Platform focus on Cmpd Mgmt & HTS first
Our main immediate need: classic medchem: small number of molecules screened against panel of diverse assays
Spreadsheets and Spotfire only work so far for sharing data with biologists/ chemists/ screeners
Our research program is a ‘mixture’ of Broad-registered compounds and some ‘external’--hence, need for separate compound registration system (CDD--in progress; as separate ‘collaborative’development contract)
No current mechanism to readily view, mine and compare data frommultiple types of assays
Solution (‘interim’?): CDD
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Acknowledgments, part 1Genetics
(MGH/SC)Pamela SklarShaun PurcellRoy PerlisJordan SmollerMark DalyJennifer BarnettKimberly ChambertJinbo FanManuel FerreiraAndrew KirbyYan MengJennifer MoranMatt OgdieDouglas RuderferJennifer StoneKathe Todd-BrownLori ThomasLauren Weiss
Chemical BiologySteve Haggarty
(MGH/SC)Jen PanJon MadisonDan FassKrista HennigJosh KettermanIren KurtserXiulin Liu Cat LuceThomas NielandStephanie NortonSurya ReisKraig Thierault
NeurobiologyLi-Huei Tsai(MIT/SC)Ji-Song GuanYingwei Mao
BehaviorTracey Petryshen
(MGH/SC)Erin BerryMelanie LeussisMike LewisMai SaitoAl Schroeder
Med. ChemistryMike MoyerEd HolsonFlorence WagnerDavid Pearlman
Broad/MIT/MGH CollaboratorsEric LanderMPG/GAP/BSP
Stacey GabrielDavid AltshulerPaul deBakkerKristen ArdlieScott MahanCasey Gates
ChemBioJay BradnerRalph MazitschekAndy SternFrank AnRobert Gould
RNAi/ ImagingDavid RootAnne CarpenterDavid Logan
Et al…
Ed Scolnick, Director of the Stanley Center
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Informatics and compoundmanagementDave DeCaprioLakshmi AkellaJacob AsieduNurgees Banu SulthanBob Brady Ph.D.Steve BrudzDan DurkinGreg GeorgeMary Pat Happ Ph.D.Santhosh KumaraswamyDennis MocciaJoshua NicholsGreg WendelDavid HoweAlex OrlovskyKaren Rose
Analytical ChemistryStephen Johnston Ph.D.Galina BeletskyChris Johnson
DOS ChemistryLisa Marcaurelle Ph.D.Damian Young Ph.D.Eamon Comer Ph.D.Siva Dandapani Ph.D.Jeremy Duvall Ph.D.Baudouin Gerard Ph.D.Ann Kelly Ph.D.Sarathy Kesevan Ph.D.Haibo Liu Ph.D.Bo Pandya Ph.D.Troy Ryba Ph.D.Byung-Chul Suh Ph.D.Jingqiang Wei Ph.D.Maurice Lee Ph.D.Carol Mulrooney Ph.D.Mark Fitzgerald Ph.D.Jean-Charles Marie Ph.D
Target IDXiaoyu Li Ph.D.Monica Schenone Ph.D.
Screening Michelle Palmer Ph.D.Nicky Tolliday Ph.D.Andy Stern Ph.D.John McGrathMyra PoleyAnita VrcicLynn VerPlank Ph.D.Frank An Ph.D.Vipat RaksakulthaiJason BurbankMelanie deSilvaPeter AspesiBrandon RahhalTyler AldredgeJosh Bittker, Ph.D.
Medicinal ChemistryMikel Moyer Ph.D.David Pearlman Ph.D.Ed Holson Ph.D.Lawrence MacPherson Ph.D.
Director, Chemical Biology Platform Michael A. Foley Ph.D.Director, Novel Therapeutics Robert Gould Ph.D.
Prior industrial experience
Acknowledgments, part 2: ChemBio at the Broad
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STEP collaboratorsBernie Devlin, Steve Faraone,Nan Laird, Matt McQueen, Vishwajit Nimgaonkar, Jordan SmollerGary Sachs, Roy Perlis
UK-US Bipolar DisorderHugh Gurling, Andrew McQuillin, Nick Bass, Jacob LawrenceU. of EdinburghDouglas Blackwood, Walter Muir, Kevin McGheeTrinity CollegeMichael Gill, Aiden Corvin, Derek Morris
NIMH Genetics InitiativeControl CollectionPablo Gejman, Alan SandersFarooq Amin, Nancy BuccolaWilliam Byerley, Robert Cloninger, Raymond Crowe, Donald Black, Robert Freedman, Douglas Levinson, Bryan Mowry, Jeremy Silverman
ISC (International Schiz. Consortium)http://pngu.mgh.harvard.edu/isc/
ICCBDUSC: Carlos and Michelle Pato, MGH: Jordan Smoller, Pamela Sklar and Roy PerlisCardiff University: Nick CraddockKarolinska: Mikael Landen, Christina Hultman, Paul Lichtenstein
Funded by:NIH, NARSAD, Herman Foundation, J&J, Merck Genome Research Foundation,Stanley Medical Research Institute
Acknowledgments, part 3
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Chemical Biology Program Model: Molecular Genetics Of Human Cognition
1) Known human illnesses with firm genetic basis and unmet medical need
2) Translation of human genetics into animal disease neurobiology
3) Develop cell + biochemical assays
Eg. Rubinstein-Taybi syndrome with mutations in CBP implicating histone acetylation in cognition
Weeber et al. (2002) Mol Interv.
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Academic Science with NIH
MLI
Prob
abili
ty
of s
ucce
ssC
umul
ativ
e C
ost
Ph IV-V(Additional indications, Safety monitoring)
Dedicated Chem-Biol
Project Team formed
Compound accepted into
Clinical Development
Target identification
Assay develop-ment Hit-to-
Probe
Screening (HTS or otherwise)
1 yr 1 yr 1 yr ~ 3 yrs 1 yr 2 yrs ~3 yrs
Ph III (Efficacy and safety in large populations)
Ph II (Dose finding, initial efficacy
in patient pop.)
Ph I (Safety)
Lead Development, Optimization
Indefinite Indefinite1.5 yrs
Regulatory review
Academic Probe/Drug Development Efforts
Dr. Chris Austin, NIH Chemical
Genomics Center
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High-throughput/high-content screening modules
• Execution of primary screens and secondary follow-up assays• Capabilities for biochemical and cell-based assays • Capabilities for high-content (imaging) and plate reader assays• Capabilities to support the early stages of GE-HTS • Throughput of ~200,000 wells/day
Dr. Nicky TollidayDr. Frank AnDr. Lynn VerPlankMeghan Bliss-
MoreauJason BurbankMelanie DeSilvaStephanie NortonJohn McGrathJessie PerksMyra PoleyKaren Rose
Broad Screening Group
Dr. Mike FoleyDr. Andy Stern
(est. Dec. 2007)
Sample size (compounds) = 100,000 - 300,000 composed of bioactives, natural products, DOS
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Lithium + Valproate: Potential Cellular Pathways Relevant to Mania + Mood
HDACvalproate
1) Inositol depletion” hypothesis (Berridge 1982)2) Inhibition of GSK-3β (Klein & Melton 1996; Beaulieu et al. 2008)
PP2A
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GOAL: Test Selective HDACi with Good PK Properties in Mania + Other Animal Models
AmphetamineInduced
Hyperactivity(other assays)
Lithium
valproate vs. HDACi
amphetamine
NH2HN
O
NH
O
O
N
Dr. Tracey PetryshenBehavioral Neurogenetics Group
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Summary: lithium/valproate project
Live-cell based assay of potentially disease relevant pathway (TCF/LEF reporter)
Have identified targets; pursuing HDACs
Insight that different HDACs may be involved in mood and memory; key assays for selectivity in place
Can look for other targets and probes
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valproate (valproic acid)
Valproate: Use In Bipolar Disorder
O
OH
1965, Lambert initiated VPA therapy for mania, using the amide salt developed for epilepsy
1975, Lambert published report emphasizing anti-manic activity and synergism with lithium
1995, FDA approval for anti-manic effects
Relevant therapeutic mechanism unknown(reported inhibition: SSA-DH, GABA-T, a-KG)
Therapeutic plasma levels of ~200-600 mM
Attenuates amphetamine-induced subjective and psychological changes in humans (energy, alertness, blood pressure)
divalproex sodium (Depakote)