Cover Picture: Discovery and Biological Activity of 6BrCaQ as an Inhibitor of the Hsp90 Protein Folding Machinery (ChemMedChem 5/2011)

Université Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, Châtenay-Malabry, France.
ChemMedChem (Impact Factor: 2.97). 05/2011; 6(5):804-15. DOI: 10.1002/cmdc.201000489
Source: PubMed


Heat shock protein 90 (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 2 b (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.

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    • "Moreover, a recent paper shows that a C-terminal modulator has repressive effects on the three proteins involved in the heat shock response, which is an added value for clinical development of these types of molecules (Wang and McAlpine, 2014). Among the derivatives of Nvb developed for their potent C-terminal domain inhibiting properties, 6-bromo-3-[4-methoxyphenylcarboxamide]-quino- lein-2-one (6BrCaQ) has shown very encouraging results in several cancer cell lines (Audisio et al., 2011b, 2014). Furthermore, this quinolinone analogue of Nvb has demonstrated its ability to stimulate both intrinsic and extrinsic apoptosis pathways through the activation of caspases 7, 8 and 9 and PARP cleavage in a breast cancer cell line, MCF-7. "
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