N-substituted azaindoles as potent inhibitors of Cdc7 kinase

被引：30

作者：

Bryan, Marian C. ^{[1
]}

Falsey, James R. ^{[1
]}

Frohn, Mike ^{[2
]}

Reichelt, Andreas ^{[2
]}

Yao, Guomin ^{[2
]}

Bartberger, Michael D. ^{[2
]}

Bailis, Julie M. ^{[3
]}

Zalameda, Leeanne ^{[4
]}

San Miguel, Tisha ^{[4
]}

Doherty, Elizabeth M. ^{[1
]}

Allen, John G. ^{[2
]}

机构：

[1] Amgen Inc, Therapeut Discovery, Med Chem Res Technol, Thousand Oaks, CA 91320 USA

[2] Amgen Inc, Therapeut Discovery, 1 Amgen Ctr Dr, Thousand Oaks, CA 91320 USA

[3] Amgen Inc, Oncol Res, San Francisco, CA 94080 USA

[4] Amgen Inc, Therapeut Discovery, Bioassay & Profiling, Thousand Oaks, CA 91320 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 07期

关键词：

Cdc7; inhibitors; Azaindole; Cell division cycle; Conformational analysis; CELL-DIVISION CYCLE; DNA-REPLICATION; CANCER-THERAPY; CHECKPOINT; PYRROLOPYRIDINONES; INITIATION; DISCOVERY; LINES;

D O I：

10.1016/j.bmcl.2013.02.007

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Cdc7 kinase is responsible for the initiation and regulation of DNA replication and has been proposed as a target for cancer therapy. We have identified a class of Cdc7 inhibitors based on a substituted indole core. Synthesis of focused indole and azaindole analogs yielded potent and selective 5-azaindole Cdc7 inhibitors with improved intrinsic metabolic stability (ie 36). In parallel, quantum mechanical conformational analysis helped to rationalize SAR observations, led to a proposal of the preferred binding conformation in the absence of co-crystallography data, and allowed the design of 7-azaindole 37 as a second lead in this series. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：2056 / 2060

页数：5

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