Discovery of XL888: A novel tropane-derived small molecule inhibitor of HSP90

被引：54

作者：

Bussenius, Joerg ^{[1
]}

Blazey, Charles M. ^{[1
]}

Aay, Naing ^{[1
]}

Anand, Neel K. ^{[1
]}

Arcalas, Arlyn ^{[1
]}

Baik, TaeGon ^{[1
]}

Bowles, Owen J. ^{[1
]}

Buhr, Chris A. ^{[1
]}

Costanzo, Simona ^{[1
]}

Curtis, Jeffrey K. ^{[1
]}

DeFina, Steven C. ^{[1
]}

Dubenko, Larisa ^{[1
]}

Heuer, Timothy S. ^{[1
]}

Huang, Ping ^{[1
]}

Jaeger, Christopher ^{[1
]}

Joshi, Anagha ^{[1
]}

Kennedy, Abigail R. ^{[1
]}

Kim, Angie I. ^{[1
]}

Lara, Katherine ^{[1
]}

Lee, Jae ^{[1
]}

Li, Jonathan ^{[1
]}

Lougheed, Julie C. ^{[1
]}

Ma, Sunghoon ^{[1
]}

Malek, Shiva ^{[1
]}

Manalo, Jean-Claire L. ^{[1
]}

Martini, Jean-Francois ^{[1
]}

McGrath, Garth ^{[1
]}

Nicoll, Monique ^{[1
]}

Nuss, John M. ^{[1
]}

Pack, Michael ^{[1
]}

Peto, Csaba J. ^{[1
]}

Tsang, Tsze H. ^{[1
]}

Wang, Longcheng ^{[1
]}

Womble, Scott W. ^{[1
]}

Yakes, Michael ^{[1
]}

Zhang, Wentao ^{[1
]}

Rice, Kenneth D. ^{[1
]}

机构：

[1] Exelixis Inc, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 17期

关键词：

HSP90; Inhibitor; XL888; Tropane; Cancer; SHOCK-PROTEIN; 90; HEAT-SHOCK-PROTEIN-90; INHIBITORS; KINASE DOMAIN; CHAPERONE; GELDANAMYCIN; BIIB021; POTENT; RAF;

D O I：

10.1016/j.bmcl.2012.07.052

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：5396 / 5404

页数：9

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