Alternative approaches to Hsp90 modulation for the treatment of cancer

• Published in: Future medicinal chemistry Vol. 6; no. 14; p. 1587
• Main Authors: Hall, Jessica A, Forsberg, Leah K, Blagg, Brian S J
• Format: Journal Article
• Language: English
• Published: England 01.09.2014
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Catechin - analogs & derivatives; Catechin - chemistry; Catechin - pharmacology; Drug Discovery; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - chemistry; HSP90 Heat-Shock Proteins - metabolism; Humans; Models, Molecular; Neoplasms - drug therapy; Neoplasms - metabolism; Novobiocin - analogs & derivatives; Novobiocin - pharmacology; Silymarin - chemistry; Silymarin - pharmacology
• ISSN: 1756-8927
• DOI: 10.4155/FMC.14.89

Hsp90 is responsible for the conformational maturation of newly synthesized polypeptides (client proteins) and the re-maturation of denatured proteins via the Hsp90 chaperone cycle. Inhibition of the Hsp90 N-terminus has emerged as a clinically relevant strategy for anticancer chemotherapeutics due to the involvement of clients in a variety of oncogenic pathways. Several immunophilins, co-chaperones and partner proteins are also necessary for Hsp90 chaperoning activity. Alternative strategies to inhibit Hsp90 function include disruption of the C-terminal dimerization domain and the Hsp90 heteroprotein complex. C-terminal inhibitors and Hsp90 co-chaperone disruptors prevent cancer cell proliferation similar to N-terminal inhibitors and destabilize client proteins without induction of heat shock proteins. Herein, current Hsp90 inhibitors, the chaperone cycle, and regulation of this cycle will be discussed.