Download - The NIH Chemical Genomics Center
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Christopher P. Austin, M.D.Director, NIH Chemical Genomics Center
National Institutes of Health
Visit of UK House of Lords 4 June 2008
The NIH Chemical Genomics Center
Bringing Biopharmaceutical Technologies to Academic Chemical Biology and Drug
Discovery
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The best of times, the worst of times
How to translate the genome into biological insights and therapeutics?
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The “Non-Druggable”
Genome Problem
GPCRsEnzymesIon Channels
Other
Unknown
46%
Drews, J. (2000) Science 287:1962
Venter et al., (2001) Science 291:1304
(n=483)
Receptor (1543, 5%)
Nuclear Receptors
Drug Target Classes Human Genome
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“…To empower the research community to use small molecule compounds in their research, whether as tools to perturb genes and pathways, or as starting points to the development of new therapeutics for human disease.”
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The Molecular Libraries Roadmap: An Integrated Initiative
Molecular LibrariesScreening Centers
Network (MLSCN)
Compound Repository(MLSMR)
Instrumentation
ChemicalDiversity
AssayDevelopment
PredictiveADMET
Technology Development Data Production Data Analysis/Dissemination
CheminformaticsResearch Centers
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Unique features of the MLSCN
All Centers screen same compound collectionAllows comparison of compounds’ activities in many assays
Capability to screen very wide variety of assay typesMedicinal chemistry to transform hits into probes
Chemical probes of gene, pathway, and cell functionsData are released without restriction
PubChem: Screening dataProbe reports: activity, SAR, purity, compound source data Enabling for all researchers to use probes and compute on the dataSharing is catalytic to the transformation of data into information
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http://mli.nih.gov
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DC = Diversity CompoundsNC = Non-commercialTL-KIN = Kinase Targeted LibraryTL-GPCR = GPCR Targeted LibraryTL-IC = Ion Channel Targeted Library
TL-PRO = Protease Targeted LibraryTL-NUC = Nuclear Receptor Targeted TL-NTP = National Toxicology Program SS = Known BioactivesNP = Natural ProductsDEA = DEA Controlled Substances
MLSMR Compound Collection (260,000 Compounds)
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NIH Chemical Genomics Center
Founded 200454 scientists – biologists, chemists, informaticians, engineersCollaborates with >100 investigators worldwide
60% NIH extramural25% NIH intramural15% Foundations, Research Consortia
Focus on novel targets, rare and orphan diseases
Equal number of projects for basic research chemical probes and starting points for disease drug development
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NIH Chemical Genomics Center: Founding Principles
Bring the best of the technologies, equipment, experience, and people from pharma and biotech, and apply them to the 95% of the genome and 95% of human diseases not worked on by biopharmaScale must be equal to or greater than a pharmaAutomate everything
Cheaper, faster, more accurateAllows recruitment and retention of finest scientists
Collaborate extremely widelyProduce chemical probes of demonstrated biological utility
Requires major Medicinal Chemistry presence
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NCGC Staff May 2008
Scientific and Admin Management, 6 Lab Operations, 2 Automation and Cmd Mgt,
6
Chemistry, 15
Informatics, 7
Assay Development and Biology, 18
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AssayPeer review
Candidate Probe
Optimization Chemistry
NCGC Operation
Screen Data
Adequate potency and solubility?
YES
NO
Bioassay
Investigator
Optimize Assay
Compound Repository
Advice
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Disease areas of NCGC projects 2005-2007
Other5%
Genetic Diseases5%
Metabolic Diseases5%
Toxicology7% Basic Research
36%
Cancer23%
InfectiousDiseases
11%
Neuroscience8%
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Establishing a paradigm for chemical genomics
For each assay, efficiently and comprehensively describe the biological activity of a chemical library
1. Direct us toward chemical series: • suitable probes• probe potential
SAR for probe optimization
2. Populating a “Chemical Genomics” database • reliable activity of all library membersfor all assays that are screened at NCGC•
→
useful for profiling actives against all
subsequent assays
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•
Conventional HTS: done at one concentration (typically 10 uM)•
qHTS: All compounds tested in titration –
15 concentrations –
Concentration range 0.5 nM
to 92 uM–
Concentration-response curve generated for each compound•
Assay volumes ~5 uL•
1536-well plate format•
Informatics pipeline for data processing, curve fitting & classification•
Higher quality data
Compound concentration
Quantitative high-throughput screening (qHTS)
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Lower confidence data
qHTS curve classification criteriaCurve Class Description Efficacy r2 Asymptotes Inflection
1* Complete curve (a)Partial curve (b)
> 80% (a)≤
80% (b)≥
0.9 2 yes
2† Incomplete curve > 80% (a)< 80% (b)
> 0.9 (a)<
0.9 (b)1 yes
3 Single pt activity > Min‡ NA 1 no
4 Inactive NA NA 0 no
NOTES: *AC50 derived from data; †AC50 extrapolated from data; ‡Min is > 3 SD from the mean activity of the sample field at the highest tested concentration
1a 1b 2a 2b 3 4
Examples
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Derivation of nascent SAR from qHTS
•
Class 1 and 2a –
Hierarchical clustering–
Leadscope fingerprints
–
Tanimoto
cutoff = 0.7•
55 clusters
•
Maximal common substructure (MCS) extracted for each cluster–
MCS used to search entire screening collection
•
40 series composed of 4-25 active analogs–
Results associated with biological data
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O
N
N
N
N
O
Cl
OHN
N
N
Cl
O
OHN
N
N
N
N
O
N
HNO
N
N
O Cl
O
ON
O
NH2
N
N
F
ON
N
N
O
N
N
HN
O
O
H2N
NO
N
N
O
Cl
O
ON
N
N
Cl
ON
N
N
O
N
N
HN
N
N
O
O
N
HNO
N
N
O
Classes 1a, b and 2 ►12 cpdsCluster 5,
MCS
2-phenyloxazole-4-carbonitrile
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O
N
N
N
N
O
O
N
N
HN
O
O
Cl
ON
O
N
N
O
N
N
N
N
O
Cl
OHN
N
N
Cl
O
OHN
N
N
N
N
O
N
HNO
N
N
O
Cl
O
ON
O
NH2
N
N
F
ON
N
N
O
N
N
HN
O
O
H2N
NO
N
N
O Cl
O
ON
N
N
Cl
ON
N
N
O
N
N
HN
N
N
OO
N
HNO
N
N
O
Cl
OHN
O
N
N
O
N
N
N
N
O
O
N
N
HN
N
O
O
N
N
HN
O
Cl
O
OHN
N
N
N
N
Cl
O
OHN
N
N
NO
N
N
N
N
O
O
N
N
HN
O
Cl
ON
N
N
Cl
OHN
N
NCl
ON
O
N
N
O
N
N
HN
O
O
HNO
N
N F
OHN
N
N
N
Cl
ON
N
N
Cl
OHN
O
N
NCl
OHN
O
N
N
F
ON
N
NCl
ON
N
N
O
HNO
N
N
O
Cl
OHN
O
N
N
Class 1a, b and 2 ►12 cpds
Class 2b and 3 ►8 cpds
Class 4 ►16 cpds
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Cl
O
ON
O
NH2
N
N
F
ON
N
N
Classes 1a, b and 2 ►12 cpds, Cluster 5
MCS
……………1 12
Cl
OHN
O
N
N
O
N
N
HN
N
O ……………1 8
O
N
N
HN
O
O
Cl
ON
N
N……………
1 16
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Structure-Activity Relationship (SAR) Report
•
The SAR report is a ‘map’
to
enabling chemical optimization of a lead series
2-phenyloxazole-4-carbonitrile series
R1 R2 R3
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X = [O, S, or N]
Act
ive
Che
mic
al S
erie
s Fo
r Kin
ase
Ass
ay
~300,000
Electronic counterscreens
across >100 assays
PkLuc
Pol IIIsOGTYjeEPrx2Prot
β-ThalHsp90LDR
AmpC
Series 1
Series 2
Series 3
>100
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NCGC Chemical Genomics Browser
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NCGC Stats•
174 Assays deposited in PubChem
(since Feb05)
•
Wells tested: 42.5 million–
Number of data points: 302 million
•
Concentration-response (CR) profiles: 4.4 million–
Data fields deposited into PubChem: >40M
•
32 probe projects / 34 probes/33 publications•
Screening throughput 2.5 million wells/wk
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Case Study: Development of Inhibitors of Schistosoma mansoni Peroxiredoxins
NCGC Collaboration with David Williams
Department of Biological SciencesIllinois State University, Normal, IL
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•250,000,000 infections
•20,000,000 with significant pathology
•280,000 deaths/year
•Major cause of morbidity
•Endemic in 75 countries
• > 80% infections in sub-Saharan Africa
Schistosomiasis
WHO/TDR
CDC©
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Targeted Redox Pathway
Superoxide dismutase
CatalaseGlutathione peroxidasePeroxiredoxine-
O2 O2*- H2 O2 H2 O
OH* / OCl- tissue damage death
Humans have three enzymes that degrade hydrogen peroxide made from superoxide radicals
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Targeted Redox Pathway
• S. mansoni has no catalase
or glutathione peroxidase.•
Survives in humans due to parasite-specific peroxiredoxin
that degrades reactive oxygen species produced by human innate immune response.
Superoxide dismutasee-
O2 O2*- H2 O2 H2 O
OH* / OCl- Schistosome death
CatalaseGlutathione peroxidasePeroxiredoxin
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O2 O2*- H2 O2 H2 O
OH* / OCl- Schistosome death
Targeted Redox Pathway
Inhibition of S. mansoni peroxiredoxin
would prevent worm degradation of hydrogen peroxide and kill schistosomes
Superoxide dismutasee-
CatalaseGlutathione peroxidasePeroxiredoxin
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Discovery of Pathway: 2002
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Identification of Target: 2006
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Quantitative HTS:2007
•
70,000 compounds at 7 concentrations (qHTS)–
Dose-response curve for all compounds (PNAS 103, 11473-8 (2006))
–
~10,000,000 data points (16 Time-Point Reads)–
31 hours of robot time•
Results: 100 compounds with IC50 < 40 µM–
71 compounds–
6 different structural classes
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Report of chemical probes: Jan 2008
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Livers of treated mice
Treated worms
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MORE
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Full Concentration-Response
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SGC Collaboration: Chemical Probes of Gene Families
•
Discussions started 4Q 2004 (Edwards)•
Dehydrogenases
(SGC-Oxford) chosen as first
targets, enzymes received 1Q 2006–
4 enzymes screened against the full collection
•
Collaboration expanded 2Q 2007 to new targets from all SGC sites
•
Epigenetics
collaboration begun 4Q 2007–
Joint application to WT submitted last week
•
NCGC PIs–
Anton Simeonov
–
Doug Auld (Human PK)
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N
N
HNR
R
Aminoquinazolines
High Content Scaffold ‘Family’ Profiling of SGC Target Familiesp450 profiling Other NCGC assaysSGC
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hpgd selectiveIC50 = 0.11 uM
N
N
HNR
R
Aminoquinazolines
High Content Scaffold ‘Family’ Profiling of SGC Target Familiesp450 profiling Other NCGC assaysSGC
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hpgd selectiveIC50 = 0.11 uM
N
N
HNR
R
Aminoquinazolines
High Content Scaffold ‘Family’ Profiling of SGC Target Families
aldh1a1 selectiveIC50 = 1.4 uM
p450 profiling Other NCGC assaysSGC
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hpgd selectiveIC50 = 0.11 uM
fluorescent compoundN
N
HNR
R
Aminoquinazolines
High Content Scaffold ‘Family’ Profiling of SGC Target Families
aldh1a1 selectiveIC50 = 1.4 uM
p450 profiling Other NCGC assaysSGC
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N
N
HNR
R
Aminoquinazolines
High Content Scaffold ‘Family’ Profiling of SGC Target Familiesp450 profiling Other NCGC assaysSGC
Profile across all bioactivity, spectroscopic properties,aggregation assay platforms
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N
N
HNR
R
Aminoquinazolines
High Content Scaffold ‘Family’ Profiling of SGC Target Familiesp450 profiling Other NCGC assaysSGC
-
Profiles mined for each scaffold tested, known drugs, etc
-Annotated assays organized by: biological relationships,assay platform, oractivity profiles
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Education
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Public Sector
Science Pre-MLI
Probes are just the start of drug developmentPr
obab
ility
of
suc
cess
Cum
ulat
ive
Cos
t
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 Ph II Ph ILead Development, Optimization
Indefinite Indefinite1.5 yrs
Regulatory review
Clinical Trials
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Public Sector
Science with 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
Probes are just the start of drug development
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The NIH Chemical Genomics Center
•
Doug Auld•
Wei Zheng•
Anton Simeonov•
Ron Johnson•
Menghang Xia•
Ya-Qin Zhang•
Pingjun Zhu•
Henrike Veith•
Steve Titus•
Michelle Cho•
Lena Schultz •
Jennifer Wichterman•
Natasha Thornea
•
Ke Liua
•
Sunita Shuklaa
•
Wendy Leaa
•
Masaaki Sakuraib•
Sean Jeffriesc
•
Craig Thomas•
Bill Leister•
Wenwei
Huang•
Dave Maloney•
Juan Marugan•
Jack Jiang•
Bryan Mott•
Jeremy Smith•
Anjali
Bain•
Chris Leclaira
•
Amanda Skoumbourdisa
•
Ganesha Bantukallua
•
Will Maguired
•
Liz Clined
Biology
NIH Roadmap for Medical Research and the Intramural program of the NHGRI
•
Ajit Jadhav•
Yuhong Wang•
Noel Southall•
Ruili
Huang•
Joe Talafous•
Ryan MacArthur•
Trung
Nguyen
Informatics
•
Sam Michael •
Adam Yasgar•
Paul Shinn•
Carleen
Klumpp•
Jean Dehdashti
Engineering-Compound Mgt.
Chemistry
•
Chris Austin•
Jim Inglese
•
Allison Peck
Management
Outreach
aPosdocbVisiting
FellowcGrad
studentdIRTA
Administration•
Denise Philippi•
Mike Philippi•
Cathy Anzick•
Julius Ofiaza•
Peggy McClelland
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More Information
www.NCGC.nih.gov
www.MLI.nih.gov