Discovery of XL413, a potent and selective CDC7 inhibitor

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• 作者：Elena S. Koltun ; ^{elena@numerate.com} ; Amy Lew Tsuhako ; David S. Brown ; Naing Aay ; Arlyn Arcalas ; Vicky Chan ; Hongwang Du ; Stefan Engst ; Kim Ferguson ; Maurizio Franzini ; Adam Galan ; Charles R. Holst ; Ping Huang ; Brian Kane ; Moon H. Kim ; Jia Li ; David Markby ; Manisha Mohan ; Kevin Noson ; Arthur Plonowski ; Steven J. Richards ; Scott Robertson ; Kenneth Shaw ; Gordon Stott ; Thomas J. Stout ; Jenny Young ; Peiwen Yu ; Cristiana A. Zaharia ; Wentao Zhang ; Peiwen Zhou ; John M. Nuss ; Wei Xu ; Patrick C. Kearney
• 关键词：CDC7 kinase inhibitor ; CK2 inhibitors ; Benzofuropyrimidinone ; Cell cycle arrest
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 June, 2012
• 卷：22
• 期：11
• 页码：3727-3731
• 文件大小：1516 K

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 (class="boldFont">14), which was advanced into Phase 1 clinical trials. Starting from advanced lead class="boldFont">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.