Discovery of XL413, a potent and selective CDC7 inhibitor

被引：70

作者：

Koltun, Elena S. ^{[1
]}

Tsuhako, Amy Lew ^{[1
]}

Brown, David S. ^{[1
]}

Aay, Naing ^{[1
]}

Arcalas, Arlyn ^{[1
]}

Chan, Vicky ^{[1
]}

Du, Hongwang ^{[1
]}

Engst, Stefan ^{[1
]}

Ferguson, Kim ^{[1
]}

Franzini, Maurizio ^{[1
]}

Galan, Adam ^{[1
]}

Holst, Charles R. ^{[1
]}

Huang, Ping ^{[1
]}

Kane, Brian ^{[1
]}

Kim, Moon H. ^{[1
]}

Li, Jia ^{[1
]}

Markby, David ^{[1
]}

Mohan, Manisha ^{[1
]}

Noson, Kevin ^{[1
]}

Plonowski, Arthur ^{[1
]}

Richards, Steven J. ^{[1
]}

Robertson, Scott ^{[1
]}

Shaw, Kenneth ^{[1
]}

Stott, Gordon ^{[1
]}

Stout, Thomas J. ^{[1
]}

Young, Jenny ^{[1
]}

Yu, Peiwen ^{[1
]}

Zaharia, Cristiana A. ^{[1
]}

Zhang, Wentao ^{[1
]}

Zhou, Peiwen ^{[1
]}

Nuss, John M. ^{[1
]}

Xu, Wei ^{[1
]}

Kearney, Patrick C. ^{[1
]}

机构：

[1] Exelixis, Dept Drug Discovery, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 11期

关键词：

CDC7 kinase inhibitor; CK2; inhibitors; Benzofuropyrimidinone; Cell cycle arrest; PROTEIN-KINASE CK2; SCHIZOSACCHAROMYCES-POMBE; REPLICATION CHECKPOINT; CRYSTAL-STRUCTURE; CDC7-DBF4; KINASE; S-PHASE; SWI1;

D O I：

10.1016/j.bmcl.2012.04.024

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：3727 / 3731

页数：5

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