NIH Molecular LibrariesNIH Molecular LibrariesAdvancing Science through Probe Development

Carson Loomis

Molecular Libraries Program:Molecular Libraries Program: More Than A Collection Of Screening Centers

Target ID

Assay Development HTS Ph Ph II Ph Ph IIIIIIHit (Probe) 

to Lead Ph Ph IIII Ph Ph IVIV

Lead Optimization

Disease Target PrePre‐‐ClinicalClinical

IND

NDA

NIH ClinicalCenter, CTSAs

NIH RAID

NIH TRN

D

NIH Molecular Libraries Initiative NNInitiative

Molecular Libraries Program Goals:

Discover and develop small molecule chemical probesDiscover and develop small molecule chemical probes Probes: research tools for novel biological targets and 

pathways New paradigms for assay development and screeningp g y p g Focus on novel assays and targets and rare or neglected diseases Expand disease areas where small molecule tools apply to basic biology

New chemistry for small molecules and natural products probes 

Generate public comprehensive datasets Establish public sharing of SAR data. Establish a large collection of novel small molecules

2

Establish a large collection of novel small molecules

2004 2005 2006 2007 2008 Sept 2008 2009 2010 2011 2012

Molecular Libraries Program – Pilot, Production, Transition PhasesMolecular Libraries Program – Pilot, Production, Transition Phases

NCGC

Small Molecule Repository (MLSMR)

PubChem

Screening CentersScreening Centers Probe Production Centers (MLPCN)Probe Production Centers (MLPCN)

Small Molecule Repository (MLSMR)

Technology Development: Assay Development, Chemical Diversity, Instrumentation

NIH Molecular Libraries Program

Small Molecule C ll ti

Assays ChemistryCollection

• Repository • Library Enrichment

• HTS ready (R01)

• Fast Track• Fast Track• Extended characterization

MLPCNScreening/Informatics Chemistry

Comprehensive Centers Probes, Comprehensive CentersSpecialized Screening Centers Specialized Chemistry Centers

,Leads

Data Analysis/DisseminationData• PubChem

• Probe Reports, Publications, • NCBI Bookshelf

Data

Molecular Libraries Probe Production Centers Core CapabilitiesCore Capabilities• Burnham ‐ biochemical, cell‐based, HCS assays; NMR based ligand optimization, PK/ADME

• Broad ‐ biochemical, cell‐based, HCS assays, automated microscopy, small molecule microarray, BSL‐2

• NCGC – qHTS, enzyme, protein‐protein, BSL‐2 assays, HCS• Scripps GPCRS protein protein enzyme ion channel

Comprehensive centers

• Scripps – GPCRS, protein‐protein, enzyme, ion channel, reporter assays; PK/ADME

JHU i h l t t h b id t t d t h• JHU – ion channels, yeast two‐hybrid assays; automated patch clamp

• UNM – HT flow cytometry; real time kinetic analysis, cell/bead based multiplex assays

Specialized screening 

• Southern Research Institute – BSL‐2/3 containment assays for viruses and bacteria

centers

• Kansas ‐ HT analytical, preparative scale synthesis; virtual library enumeration; in silico properties

• Vanderbilt ‐ HT analytical, preparative scale synthesis; DMPK; 

Specialized chemistry  a de b t a a yt ca , p epa at e sca e sy t es s; ;

virtual library enumeration; in silico propertiescenters

Molecular Libraries Small Molecule Repository

Molecular Libraries Probe Production Center Network MLPCN

Compounds from the SMR

HTS Assays from the Community

380,000~400 projects

MLPCN S iMLPCN Screening Centers Network 

Academic

TargetHTS S Ch t i Chemistry

MLPCN

Academic Investigators

MLSMR

HTS Screen Characterize ChemistryHits SAR Probes

CPDP CPDP Update Probe Report Evaluation

MLSMR

What is the Compound Probe Development Plan (CPDP)?What is the Compound Probe Development Plan (CPDP)? Plan for the initial implementation of a screening campaign Developed by the ML Screening Center and the Assay Provider

ML S i N t kANNUAL 2011 PROGRAM

ML Screening NetworkANNUAL 2011 PROGRAM(June 2011 /May 2012) (2004‐2011)

Screening NetworkAssigned Projects 125 646Assigned Projects 125 6461° Screens 96 468Probes 64 297Direct Publications 123 487

Assay Recruitment

R03 Projects Assigned 58 (cycle 18‐20) 512

Assay Fast Tracks 28 124

Chemistry Fast Tracks 10 14

Research Fields of MLP Projects (2005‐2012)

Neuroscience 17.1%

Allergy and 

General Medical Sciences 14.5%

Diabetes/Metabolic/Endocrine 

7.8%gy

Infectious 23.6%

Heart/Lung/Blood 5.4%

Cancer 27.7%

Arthritis/Muscle/Skin 2.8%

Aging 0.9%

Developmental Health 0.2%

MLP Assay Class (2005‐2012)

Protein‐Protein I t ti 11%

Ion Channel, 3%Interaction, 11%

GPCR, 9%Protein‐

Nucleotide interaction, 2%

Transporter, 2%

Nuclear Receptor, 

Enzyme, 32% 2%Protein 

conformation, 2%ChaperoneChaperone 

Protein, 1%

Whole i 1%

Cellular Pathway

organism, 1%

Compound Profiling 1%Cellular Pathway, 

33%Profiling, 1%

NIH Molecular Libraries Program 2012

Target  Assay  HTS Ph IPh I Ph IIIPh IIIHit t L d Ph IIPh II Ph IVPh IVLead Disease  PrePre‐‐

Probes

gID

yDevelopment HTS Ph. IPh. I Ph. IIIPh. IIIHit to Lead Ph. IIPh. II Ph. IVPh. IVOptimizationTarget ClinicalClinical

Targets: 646646

Primary Assays 468

~18 monthsEngages the breadth & depth of expertise

Probes: 297

Probes to Lead:

18 monthsHTS to probeBiological tools for

target validation and drug discovery

p pin the research community

64

Lead Optimization: 32

Pre-Clinical Development:

24

Valley of Death

Clinical Development:

1

Biotechnology companies that have taken d t f MLadvantage of ML resources

Institution Project Typej ypZygogen, LLC Zebrafish 

Orphagen Pharmaceuticals  Orphan Nuclear Receptors

Chaperone, Technologies, Inc. Bacterial InhibitorsZygogen, LLC Angiogenesis Orthosystems, Inc.  GPCRProgenra, Inc. Ubiquitin Pathway

RX3 Pharmaceuticals, Inc. AntimicrobialsVala Sciences, Inc. HTS Imaging AssaysVala Sciences Inc ObesityVala Sciences, Inc. Obesity

Agios Pharmaceuticals, Inc.  Cancer Treatment

Eutropics Pharmaceuticals, Inc. Cancer TreatmentMetabolix, Inc. Kinase Assays

Outcomes of ML Discoveries

• First candidate drug RPC1063 in phase I clinical trials for muscular dystrophy

• Commercialized technology:Commercialized technology:• Hypercyt Flow Cytometry Screening

Bi t h t t• Biotech startups:• Abide Therapeutics www.abidetx.com/• Ember Therapeutics www.embertx.com/index.phpp p p• Receptos Inc. www.receptos.com/

Molecular Libraries & SBIR/STTR

ML P ill b E di i M 2014• ML Program will be Ending in May 2014• Screening and Chemistry Centers

Resource to research investigators Resource to research investigators Develop SBIR Applications