Bisarylmaleimides & the Corresponding Indolocarbazoles as Kinase Inhibitors

作     者：Scott E. Conner Harold B. Brooks Eileen Considine Jack A. Dempsey Margaret M. Faul Cathy Ogg Bharvin Patel Richard M. Schultz Charles D. Spencer Beverly Teicher Scott A. Watkins 

作者机构：Lilly Research Laboratories A Division of Eli Lilly & Company Lilly Corporate Center Indianapolis Indiana 46285 USA 

出 版 物：《合成化学》 (Chinese Journal of Synthetic Chemistry)

年 卷 期：2004年第12卷第Z1期

页      面：11-11页

学科分类：07[理学] 0703[理学-化学] 

主　　题：Bisarylmaleimides the Corresponding Indolocarbazoles as Kinase Inhibitors CDK 

摘      要：Cyclin dependent kinases (CDKs) have recently raised considerable attention because of their central role in the regulation of cell cycle progression. A high incidence of genetic mutation of CDK substrates and deregulaton of CDK modulators were found in a number of disease states,particularly in cancer. A novel series of unsymmetrical substituted indolocarbazoles were synthesized and their kinase inhibitory capability was evaluated in vitro. 6-Substtuted indolocarbazoles were found to be highly potent and selective D1/CDK4 inhibitors. These indolocarbazoles exhibited ATP competitive D1/CDK4 activity and inhibited tumor cell growth,arrested tumor cell at G1 phase. These molecules demonstrated potent anti-tumor activity and inhibited pRb phosphorylation at S780 in the human lung carcinoma (Calu6) and non-small cell lung carcinoma (NCI-H460) xenograft models. The results indicate that these small molecules have potential as therapeutic agents in cancer chemotherapeutc agents.