title: Design, synthesis, and evaluation of small molecule Hsp90 probes.
abstract: A number of compounds from different chemical classes are known to bind competitively to the ATP-pocket of Hsp90 and inhibit its chaperone function. The natural product geldanamycin was the first reported inhibitor of Hsp90 and since then synthetic inhibitors from purine, isoxazole and indazol-4-one chemical classes have been discovered and are currently or soon to be in clinical trials for the treatment of cancer. In spite of a similar binding mode to Hsp90, distinct biological profiles were demonstrated among these molecules, both in vitro and in vivo. To better understand the molecular basis for these dissimilarities, we report here the synthesis of chemical tools for three Hsp90 inhibitor classes. These agents will be useful for probing tumor-by-tumor the Hsp90 complexes isolated by specific inhibitors. Such information will lead to better understanding of tumor specific molecular markers to aid in their clinical development. It will also help to elucidate the molecular basis for the biological differences observed among Hsp90 inhibitors.
authors: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, United States.
authors: Tony
authors: T
authors: Taldone
authors: Danuta
authors: D
authors: Zatorska
authors: Pallav D
authors: PD
authors: Patel
authors: Hongliang
authors: H
authors: Zong
authors: Anna
authors: A
authors: Rodina
authors: James H
authors: JH
authors: Ahn
authors: Kamalika
authors: K
authors: Moulick
authors: Monica L
authors: ML
authors: Guzman
authors: Gabriela
authors: G
authors: Chiosis
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects*; D006801:Humans; D015335:Molecular Probes / Q000138:chemical synthesis
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D015335:Molecular Probes