N-substituted azaindoles as potent inhibitors of Cdc7 kinase

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• 作者：Marian C. Bryan^a ; James R. Falsey^a ; Mike Frohn^b ; Andreas Reichelt^b ; Guomin Yao^b ; Michael D. Bartberger^b ; Julie M. Bailis^c ; Leeanne Zalameda^d ; Tisha San Miguel^d ; Elizabeth M. Doherty^a ; John G. Allen^b ; ^{johallen@amgen.com}
• 关键词：Cdc7 inhibitors ; Azaindole ; Cell division cycle ; Conformational analysis
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：1 April, 2013
• 年：2013
• 卷：23
• 期：7
• 页码：2056-2060
• 全文大小：1082 K

文摘

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.