Goals & Rationale
The NIH Roadmap Molecular Libraries Program (MLP) is a
research program designed to:
• discover & develop small molecule chemical probes to be used as
research tools to interrogate existing and novel biological targets and
pathways
• Generate comprehensive datasets in PubChem to study compound
structure – biological function
Urgent need to determine functions of genes
•  Chemical Probes complementary to molecular genetic tools
Urgent need to catalyze development of therapeutics for rare
and orphan diseases
•  >6000 rare diseases w/ known genetic basis, but < 100 available
treatments
Not “drug discovery” but probes may serve as starting points for
translational research & drug discovery/development
Molecular Libraries Probe
Production Centers Network (MLPCN)
Molecular Libraries Small
Molecules Repository (MLSMR)
(BioFocus DPI, So. SF, CA)
+
9 centers
funded across the country:
4 COMPREHENSIVE CENTERS:
-Covers the complete chemical probe development process from
assay development to chemical synthesis of potent and selective
probe compounds
Burnham,
Broad Institute,
Scripps,
NCGC
5 SPECIALIZED SCREENING CENTERS:
-Focus on specific type of assays. Smaller in scope.
John Hopkins- Ion Channel Center,
Southern Research- Specialized Biocontainment (BSL-3)
University of New Mexico Center for Molecular Discovery-Flow
Cytometry assay
SPECIALIZED CHEMISTRY CENTERS:
-Covers Cheminformatics, Med Chemistry & limited pharmacology
University of Kansas,
Vanderbilt Specialized Chemistry Center
MLP Grant Programs
1)
R03 (PAR-09-129) mechanism: HTS Ready Assays
“Solicitation of Assays for High Throughput Screening (HTS) in the Molecular Libraries Probe
Production Centers Network (MLPCN) (R03)”
http://grants.nih.gov/grants/guide/pa-files/PAR-09-129.html
2)
R21 (PAR-10-182) mechanism: (reissue of PAR-08-024): Assay Development
“Assay Development for High Throughput Molecular Screening (R21)”
http://grants.nih.gov/grants/guide/pa-files/PAR-10-182.html
Also browse the NOT-RM-09-008: Guidance on Submitting Applications to PAR-08-024:
http://grants.nih.gov/grants/guide/notice-files/NOT-RM-09-008.html
3)
Fast Track Entry (NOT-RM-09-011) extension - Existing NIH Grant
“Notice of Opportunity for Fast Track Entry of Assay Projects for High Throughput
Screening into the NIH Roadmap Molecular Libraries Probe Production Centers Network”
http://grants.nih.gov/grants/guide/notice-files/NOT-RM-09-011.html
4)
R01 (PA-10-213) mechanism (reissue of PA-07-320): Assay Development (NIDDK)
“Development of Assays for High-Throughput screening for use in Probe and Pretherapeutic Discovery (R01)”
http://grants1.nih.gov/grants/guide/pa-files/PA-10-213.html
MLP Grant Programs
PI applies
Year 1
R03
Awarded within
Year 1
PI applies
R21
2 application
Dates per year
Reviewed
Within
6 months
‘Fast
Tracked”
$100K
(Direct cost)
Monthly
Review
by NIH SO
Awarded within
9 months
-
PI has an Basic Res R01
Grant w/ Assay Dev & HTS
as embedded aims
PI applies
R01
n Years (up to 3)
R01
NIDDK
3 application
Dates per year
(std R01 dates)
‘Fast
Tracked”
PI applies
Reviewed
Within
6 months
in $250K modules
(Direct cost)
Awarded within
9 months
-
Year 2
$25K + $25K 2nd yr
(Direct cost)
Total = $50K
9 – 10 months
Reviewed
Within
6 months
3 application
Dates per year
+
Monthly
Review
by NIH SO
‘Fast
Tracked”
Monthly
Review
by NIH SO
Year 2
“FT“ R03 $25K
(Direct cost)
Total = $125K
Year 1
“FT“ R01” no $
MLPCN screens ~300K
NIH MLSMR at No cost to PI
Year n + 1
“FT“ R01” no $
MLPCN screens ~300K
NIH MLSMR at No cost to PI
Project
period:
(R03) Updated $4MM & 60-100 grants/yr
HTS-ready assay (triannual) Exp. 5Jan12
(R21) $6MM ~30 grants in 2011
Assay development (biannual) Exp. 30Oct10
Funding
Direct: $25K for 1st yr + $25K for 2nd year
Direct: up to $100K for 1st yr + $25K 2nd yr (FT)
Use of
Funds
include
Collaborative activities between Center and Assay
Provider: travel to Screening center, hit follow-up in
AP’s lab w/ 2°, 3° assays (e.g. countersreens &
biological validation assays), reagent prep requiring
specialized expertise of AP lab
Support (internal & external) for all 1°, 2°, 3° assay
development & pilot screen to R03 “HTS ready”
status. Cell lines & reagents development.
Minimum
Reqmts
- Proven HTS assay readiness:
- Preliminary data - pilot screen required.
-96-well plate format as a minimal (384-preferred)
-Assay has >0.5 Z’ parameter, S/B >5, <10%CV
-Reproducible dose-dependent responses w/
standard pharmacophores, substrates or inhibitors
-Control parameter: time, temp, protein
concentration dependencies & 0.1 -1% DMSO
tolerance
-Reagent availability, stability to storage & assay
-Plate-to-plate & day-to-day assay performance
-Strong rationale for how a unavailable, novel,
selective & potent pharmacological probe would
appropriately address an Investigators’ ongoing
research question
-Define the requisite attributes of this probe
-Provide a screening plan of assays to select small
molecules structures with essential probe attributes
from large chemical libraries & rule out artifacts
-Reagents & readouts & proposal to achieve HTS at
R03 like performance level & current data status
-If 1° assay is well developed, define , 2°, 3° assay
development needs & plans
Res.Sec.
Restricted to 6 pages
Restricted to 6 pages
Deadline
3Sep10, 4Jan11, 4May11, 2Sep11 & 4Jan12
29Jun10 & 29Oct10
Peer Rev
Nov 2010, Mar2011, Jul 2011, Nov 2011, Mar 2012
Oct 2010 & Feb 2011
Council
Jan 2011, May 2011, Oct 2011, Jan 2012, May 2012
Jan 2011 & May 2011
Start
Jun 2011, Sep 2011, Feb2012, Jun 2012, Sept 2012
Apr 2011 & Jul 2011
Project
period:
Funding
Use of
Funds
include
Minimum
Reqmts
“Fast Track”
MLP R21FT & “R01”FT
(R01) $6MM ~30 grants in 2011
$25K direct for R21FT ; NO funds for R01FT
Direct: in modules of $250K; up to 3 yrs; 90 day preaward costs allowable; >$250K full budget justficn
Assay development Exp. 8Sep13
Same as R03 for R21FT (see previous slide)
Same as for R21, but as justified by novelty and
depth of assay dev. Only pilot screens. Modular
budget < $250K; full budget justification >$250K
- Progress Report for originating grant on specific aims
as relating to assay development & screen
-  If “R01” (U01, P01, R21, RC4 etc) must be NIH peer
reviewed & have aim or statement of a target & assay
that screened
-  Exec summary on Technical Screening Criteria
-  Novelty in areas & approaches a key criterion
-  Emphasis on assays new insight into important
disease targets or indirectly related but could provide
insight into underlying disease biology & rare and
neglected diseases
-  Assays relevant to NIDDK, NCI, NHLBI, NIA, NIAAA,
NIAID, NIDA, NIGMS or NIMH, focused on specific
disease or basic physiology, cell biology or
developmental process
- Very similar to R21 requirements & criteria for technical
feasibility, automatability, screening plan, & secondary
assays
- Resulting assays eligible for FT or direct collaborations
w/ MLPCN centers
- Feasibility of screening assays
- Completeness of screening plan
- Availability of reagents
- Completion of a pilot screen
- Current availability of pharmacological probes to
proposed target or phenotype
- Assay validation package to R03 level (see previous
slide) & simple Critical path flowchart
- Publications & references describing project assays
Res.Sec.
Restricted to 6 pages (guideline)
Restricted to 12 pages
Deadline
Submit by end of 1st week of each month
Standard (renewable): Feb 5, Jun 5, Oct 5
AIDS related: May 7, Sep 7, Jan 7
Peer Rev
Only an Adminstrative review by MLP PT
Jun-Jul, Oct-Nov, Feb-Mar
Council
By 3rd week of each month
Aug, Oct, Jan, May
Start
Notification by end of month
Sep, Dec, Apr, Jul
CPCCG Capabilities and Resources:
http://www.sanfordburnham.org/default.asp?
contentID=902h
For further information contact:
Dr. Thomas “T.C.” Chung (Project Manager & Outreach Mentor)
Conrad Prebys Center for Chemical Genomics,
Sanford-Burnham Institute for Medical Research,
10901 N. Torrey Pines Road,
La Jolla, CA 92037
T 858-795-5331
Acknowledgments:
Supported by U54 HG005033-01