Synthesis, structure-activity relationship, and biological studies of indolocarbazoles as potent cyclin D1-CDK4 inhibitors

  • J Med Chem. 2003 May 22;46(11):2027-30. doi: 10.1021/jm0256169.
Guoxin Zhu  1 ,  Scott E Conner ,  Xun Zhou ,  Chuan Shih ,  Tiechao Li ,  Bryan D Anderson ,  Harold B Brooks ,  Robert Morris Campbell ,  Eileen Considine ,  Jack A Dempsey ,  Margaret M Faul ,  Cathy Ogg ,  Bharvin Patel ,  Richard M Schultz ,  Charles D Spencer ,  Beverly Teicher ,  Scott A Watkins
Affiliations
  • 1. Lilly Research Laboratories, A Division of Eli Lilly & Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. [email protected]
PMID: 12747775 DOI: 10.1021/jm0256169
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.