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Online ISSN: 1860-7187
March 10, 2011
VIP: Discovery and Biological Activity of 6BrCaQ as an Inhibitor of the Hsp90 Protein Folding Machinery
Davide Audisio, Samir Messaoudi, Lukasz Cegielkowski, Jean-François Peyrat, Jean-Daniel Brion, Délphine Methy-Gonnot, Christine Radanyi, Jack-Michel Renoir, and Mouâd Alami*
Heat-shock protein (hsp)90 is a validated novel anticancer target with unique features. As a molecular chaperone, hsp90 is implicated in maintaining the conformation, stability, activity, and cellular localization of several key oncogenic client proteins that are involved in signal transduction pathways leading to proliferation, cell-cycle progression, apoptosis, angiogenesis, and metastasis. The hsp90 protein function may be blocked by specific inhibitors, thereby freezing the chaperone cycle; this in turn decreases the affinity of hsp90 for client proteins, thus leading to proteasome-mediated degradation of oncogenic client proteins.
Collaborative research efforts conducted by chemists in the research group of Mouâd Alami and biologists in the laboratory of Michel Renoir at the University of Paris Sud (France) have led to the synthesis and discovery of a new compound, 6Br-CaQ, which has potent anticancer activity due to its capacity to destabilize several hsp90 client proteins. This was deduced from a combination of cell viability tests, flow cytometry analyses, and Western blot experiments in a panel of cancer cell lines that allow identification of the apoptotic and autophagic potential of 6Br-CaQ. Comparison with one other lead compound (4TCNA), identified previously by Alami's group, suggest that compounds from this family of hsp90 inhibitors may target a different cluster of hsp90 client proteins.
Received November 11, 2010; published online March 4, 2011, DOI: 10.1002/cmdc.201000489.