作者:Marian C. Bryan、James R. Falsey、Mike Frohn、Andreas Reichelt、Guomin Yao、Michael D. Bartberger、Julie M. Bailis、Leeanne Zalameda、Tisha San Miguel、Elizabeth M. Doherty、John G. Allen
DOI:10.1016/j.bmcl.2013.02.007
日期:2013.4
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.