Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells

被引：362

作者：

Grasberger, BL ^{[1
]}

Lu, TB ^{[1
]}

Schubert, C ^{[1
]}

Parks, DJ ^{[1
]}

Carver, TE ^{[1
]}

Koblish, HK ^{[1
]}

Cummings, MD ^{[1
]}

LaFrance, LV ^{[1
]}

Milkiewicz, KL ^{[1
]}

Calvo, RR ^{[1
]}

Maguire, D ^{[1
]}

Lattanze, J ^{[1
]}

Franks, CF ^{[1
]}

Zhao, SY ^{[1
]}

Ramachandren, K ^{[1
]}

Bylebyl, GR ^{[1
]}

Zhang, M ^{[1
]}

Manthey, CL ^{[1
]}

Petrella, EC ^{[1
]}

Pantoliano, MW ^{[1
]}

Deckman, IC ^{[1
]}

Spurlino, JC ^{[1
]}

Maroney, AC ^{[1
]}

Tomczuk, BE ^{[1
]}

Molloy, CJ ^{[1
]}

Bone, RF ^{[1
]}

机构：

[1] Johnson & Johnson Pharmaceut Res & Dev LLC, Exton, PA 19341 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2005年 / 48卷 / 04期

关键词：

D O I：

10.1021/jm049137g

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

HDM2 binds to an a-helical transactivation domain of p53, inhibiting its tumor suppressive functions. A miniaturized thermal denaturation assay was used to screen chemical libraries, resulting in the discovery of a novel series of benzodiazepinedione antagonists of the HDM2-p53 interaction. The X-ray crystal structure of improved antagonists bound to HDM2 reveals their a-helix mimetic properties. These optimized molecules increase the transcription of p53 target genes and decrease proliferation of tumor cells expressing wild-type p53.

引用

页码：909 / 912

页数：4

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