molecular targets development program, ccr, nci

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Molecular Targets Molecular Targets Development Program, Development Program, CCR, NCI CCR, NCI OMe N O O O O H 2 O 3 PO HO

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Page 1: Molecular Targets Development Program, CCR, NCI

Molecular Targets Development Molecular Targets Development Program, CCR, NCIProgram, CCR, NCI

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Page 2: Molecular Targets Development Program, CCR, NCI

Advanced BiomedicalAdvanced BiomedicalTechnologiesTechnologies

CCRClinical

Program

Molecular Targets & Molecular Oncology

Genetics & Genomics

Imaging & Biomarkers

IntegratedSystemsBiology

Immunology,Immunotherapy &

Immunoprophylaxis

HIV/AIDS

Intra

mura

l/Extra

mura

l

Translational Research at the CCR

Page 3: Molecular Targets Development Program, CCR, NCI

Center for Cancer Research

• 15 clinical branches

• 38 basic sciences laboratories

• > 330 principal investigators

Page 4: Molecular Targets Development Program, CCR, NCI

A549SNB19

MTDP

HTS Data

MTDP Mission

Lab Bench Data

Page 5: Molecular Targets Development Program, CCR, NCI

MTDP Mission

MTDP

• Collaborate with CCR investigators to develop and apply molecular target-specific assays

• Screen the NCI natural products repository and other sources of chemical diversity

• Identify and characterize target-specific compounds• Provide active compounds to collaborating labs for use as

bioprobes

Page 6: Molecular Targets Development Program, CCR, NCI

Target Consortium

Molecular

Target/Pathway

Staff Scientists

Lab ChiefsPostdoctoral Fellows

PIs

Proposal

Page 7: Molecular Targets Development Program, CCR, NCI

Initial Feasibility

• Quality control of reagents and cell lines– Reagent stability– Reagent specificity and binding characteristics– Cellular growth characteristics

• Time frame of assay– Stable end point

• Signal to noise ratio• Availability of appropriate controls• Availability of required equipment• Availability of sufficient reagents

Page 8: Molecular Targets Development Program, CCR, NCI

Priority Areas

• Screening Platforms

• Natural Products

• Protein Chemistry and Molecular Biology

• Libraries

• Imaging

• Information Technology

Page 9: Molecular Targets Development Program, CCR, NCI

Screening Platforms

Enzymatic- FRET

Protein-Protein Interactions- Time-Resolved Fluorrescence- Electrochemiluminescence

Cell-based- Colorimetric- Fluorometric- Luminescent

Cell-Imaging- GFP Translocation- GFP Expression

Page 10: Molecular Targets Development Program, CCR, NCI

Project Rationale Project Rationale

MDM2/ubiquitination

p53 induced apoptosis

gp78 ER stress response

RNaseH HIV inhibition E2A/SCL aberrant gene expression

ABCG2 multi-drug transport

RNAi/IGFR resistance to apoptosis

cKIT signal transduction

Cripto 1 cell adhesion

HDAC/DNMT epigenetic control Polo-like

kinase 1

cell cycle control

HIF-2 hypoxia response Smad 3 signal transduction

ER breast cancer cMet signal transduction

AP1 chemo-prevention

Ezrin cytoskeletal reorganization

TRAIL apoptotic synergy

MTDP Ongoing Projects

Page 11: Molecular Targets Development Program, CCR, NCI

Name of Library Source Sample Type # Samples

MTDP Isolated Compounds MTDP Pure NP 322Pure Natural Products DTP Pure NP 4486Korean Pure NPs Chungnam National University Pure NP 174Pure Natural Products BioMol Pure NP 231Actinomycete Products Ecopia Biosciences Pure NP 16Fungal Products University of Iowa Pure NP 168 5397

Natural Product Extracts DTP NP Extract 133154Iowa Extracts University of Iowa/DTP NP Extract 1884Korean Extracts Chungnam National University NP Extract 3423Cytotox Deck DTP NP Extract 1840Extract Test Plates MTDP/DTP NP Extract 168Endangered Plants Cincinnatti Zoo NP Extract 8Prefractionation Library MTDP/DTP Partially purified extract 10000 150477

CCR Compounds CCR PIs Synthetic 129BU Compounds Boston University CMLD Synthetic 1498Pitt Compounds University of Pittsburgh CMLD Synthetic 1398Kansas Compounds University of Kansas CMLD Synthetic 479Berkeley Compounds University of Cal., Berkeley Synthetic 17Rome Compounds University of Roma Synthetic 1900Morocco Compounds University of Morocco Synthetic 123UMBC Compounds UMBC Synthetic 318ICCB Bioactives BioMol Synthetic 480Kinase Library PKI Synthetic 80Structural Diversity Set DTP Synthetic 1929Mechanistic Diversity Set DTP Synthetic 879Challenge Set DTP Synthetic 49LOPAC1280 Sigma Synthetic 1280 10559

Totals 166433

Current Libraries for Screening

Page 12: Molecular Targets Development Program, CCR, NCI

NCI’s Natural Products Collections and NCI’s Natural Products Collections and Extract RepositoryExtract Repository

Terrestrial Plants-Tropical and Subtropical

Marine Invertebrates and Algae-Indopacific-Caribbean

Selected Microbial Isolates-Cyanobacteria-Fungi

> 65,000 Organisms

> 170,000 Individual Extracts-Organic Solvent Extracts-Aqueous Extracts

Collections

Extract Repository

Page 13: Molecular Targets Development Program, CCR, NCI