Synthesis,structure-activity relationship,and biological studies of indolocarbazoles as potent cyclin D1-CDK4 inhibitors |
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| Authors: | Zhu Guoxin Conner Scott E Zhou Xun Shih Chuan Li Tiechao Anderson Bryan D Brooks Harold B Campbell Robert Morris Considine Eileen Dempsey Jack A Faul Margaret M Ogg Cathy Patel Bharvin Schultz Richard M Spencer Charles D Teicher Beverly Watkins Scott A |
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| Affiliation: | Lilly Research Laboratories, A Division of Eli Lilly & Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. Zhu_Guoxin@lilly.com |
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| Abstract: | Novel substituted indolocarbazoles were synthesized, and their kinase inhibitory capability was evaluated in vitro. 6-Substituted indolocarbazoles 4 were found to be potent and selective D1/CDK4 inhibitors. 4d and 4h exhibited potent and ATP-competitive D1/CDK4 activities with IC50 values of 76 and 42 nM, respectively. Both compounds had high selectivity against the other kinases. These D1/CDK4 inhibitors inhibited tumor cell growth, arrested tumor cells at the G1 phase, and inhibited pRb phosphorylation. |
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