The hsp90 family of proteins consists of Hsp90 alpha and beta, Grp94 and Trap-1. They are abundant chaperone proteins that play roles in protein refolding and processing and the conformational maturation of several key signaling proteins, including steroid receptors, Raf kinase and several transmembrane tyrosine kinases. Hsp90 is overexpressed in tumors and may play a role in maintaining the transformed phenotype by stabilizing signaling proteins and mutated protooncogenes and by mediating tumor cell survival in hypoxic, harsh environments. Ansamycin antibiotics and radicicol are natural products that bind to a conserved pocket in the hsp90 family proteins. Occupancy of this pocket by drug alters their function and causes the degradation of the signaling proteins that require Hsp90. Addition of ansamycins to cancer cells causes RB-dependent G1 arrest, differentiation and apoptosis. Cells with defective RB function arrest in prometaphase and undergo apoptosis. One ansamycin, 17 -allylaminogeeldanamycin (17- AAG) is currently in clinical trial. The main goal of this research is to identify compounds that bind lead compounds that bind to the hsp90 pocket and have selective activities that confer novel indecence properties. A lead compound, a geldanamycin (GM) dimer has been identified with selectivity for HER-family tyrosine kinases. We have also begun to synthesize compounds designed to bind to the hsp90-family pocket and to develop chemical libraries of molecules that bind to the different hsp90 family members. These molecules will be screened for their ability to bind selectively to the chaperones, degrade specific targets, and inhibit tumor cells with particular molecular lesions. Our goal is to derive selective compounds and use them to determine the biologic effects of inhibiting each of the hsp90 family members and to identify new, target-directed drugs with anticancer activity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01CA091178-01
Application #
6334398
Study Section
Special Emphasis Panel (ZCA1-SRRB-D (J3))
Program Officer
Forry, Suzanne L
Project Start
2001-06-01
Project End
2005-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
1
Fiscal Year
2001
Total Cost
$359,780
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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