Hydrating for resistance to radicicol.
Resistance to Hsp90 inhibition has become an important concern as several clinical trials are currently in progress for the treatment of cancer. A summary of known mechanisms of resistance to Hsp90 inhibitors is provided, including the recent solution of the Humicola fuscoatra Hsp90 structure, the organism responsible for the biosynthesis of radicicol. Through careful analyses of Hsp90 structures, a plausible mechanism for resistance to Hsp90 inhibitors has been obtained by single mutations about the N-terminal ATP-binding site.
Department of Medicinal Chemistry and Specialized Chemistry Center, The University of Kansas, Lawrence, KS 66045-7563, USA.
Adam S
AS
Duerfeldt
Brian S J
BS
Blagg
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D016227:Benzoquinones / Q000737:chemistry / Q000378:metabolism; D004351:Drug Resistance / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology*
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018942:Macrolides; D000255:Adenosine Triphosphate; C035359:monorden; C001277:geldanamycin