Discovery and biological activity of 6BrCaQ as an inhibitor of the Hsp90 protein folding machinery

Heat shock protein90 (Hsp90) is a significant target in the development of rational cancer therapy, due to its role at the crossroads of multiple signaling pathways associated with cell proliferation and viability. Here, a novel series of Hsp90 inhibitors containing a quinolein-2-one scaffold was synthesized and evaluated in cell proliferation assays. Results from these structure-activity relationships studies enabled identification of the simplified 3-aminoquinolein-2-one analogue 2b (6BrCaQ), which manifests micromolar activity against a panel of cancer cell lines. The molecular signature of Hsp90 inhibition was assessed by depletion of standard known Hsp90 client proteins. Finally, processing and activation of caspases 7, 8, and 9, and the subsequent cleavage of PARP by 6BrCaQ, suggest stimulation of apoptosis through both extrinsic and intrinsic pathways. Hot stuff! A novel series of Hsp90 inhibitors containing a quinolein-2-one scaffold was synthesized and screened in cell proliferation assays. The most potent inhibitor, 6BrCaQ, exhibited strong antiproliferative activity against a panel of cancer cell lines and resulted in downregulation of Hsp90 client proteins. Moreover, 6BrCaQ induced a high level of apoptosis in MCF-7 breast cancer cells, and was found to mediate cell death in a p23-independent manner.