Alternate strategies of Hsp90 modulation for the treatment of cancer and other diseases.
The 90 kDa heat shock protein (Hsp90) has become a validated target for the development of anti-cancer agents. Several Hsp90 inhibitors are currently under clinical trial investigation for the treatment of cancer. All of these agents inhibit Hsp90's protein folding activity by binding to the N-terminal ATP binding site of the Hsp90 molecular chaperone. Administration of these investigational drugs elicits induction of the heat shock response, or the overexpression of several Hsps, which exhibit antiapoptotic and pro-survival effects that may complicate the application of these inhibitors. To circumvent this issue, alternate mechanisms for Hsp90 inhibition that do not elicit the heat shock response have been identified and pursued. After providing background on the structure, function, and mechanism of the Hsp90 protein folding machinery, this review describes several mechanisms of Hsp90 modulation via small molecules that do not induce the heat shock response.
Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas, 66045-7582, USA.
Gary E L
GE
Brandt
Brian S J
BS
Blagg
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D000255:Adenosine Triphosphate