Discovery and Biological Activity of 6BrCaQ as an Inhibitor of the Hsp90 Protein Folding Machinery

被引：43

作者：

Audisio, Davide ^{[1
]}

Messaoudi, Samir ^{[1
]}

Cegielkowski, Lukasz ^{[2
]}

Peyrat, Jean-Francois ^{[1
]}

Brion, Jean-Daniel ^{[1
]}

Methy-Gonnot, Delphine ^{[2
]}

Radanyi, Christine ^{[2
]}

Renoir, Jack-Michel ^{[2
]}

Alami, Mouad ^{[1
]}

机构：

[1] Univ Paris Sud, CNRS, Chim Therapeut Lab, BioCIS UMR 8076,Fac Pharm, F-92296 Chatenay Malabry, France

[2] Univ Paris Sud, CNRS, Lab Pharmacol Cellulaire & Mol Anticancereux, Fac Pharm,UMR 8612, F-92296 Chatenay Malabry, France

来源：

CHEMMEDCHEM | 2011年 / 6卷 / 05期

关键词：

antiproliferative agents; apoptosis; Hsp90; inhibitors; novobiocin; quinolein-2-ones; CO-CHAPERONE P23; GLYCINE-SITE; MOLECULAR CHAPERONE; TERMINAL DOMAIN; NOVOBIOCIN; HEAT-SHOCK-PROTEIN-90; RECEPTOR; COMPLEX; ANTAGONISTS; GELDANAMYCIN;

D O I：

10.1002/cmdc.201000489

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 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.

引用

页码：804 / 815

页数：12

共 63 条

[1] Modulation of chaperone function and cochaperone interaction by novobiocin in the C-terminal domain of Hsp90 - Evidence that coumarin antibiotics disrupt Hsp90 dimerization [J].