Pyrazole and pyrimidine phenylacylsulfonamides as dual Bcl-2/Bcl-xL antagonists

  • Bioorg Med Chem Lett. 2012 Jun 15;22(12):3951-6. doi: 10.1016/j.bmcl.2012.04.106.
Gretchen M Schroeder  1 ,  Donna Wei ,  Patrizia Banfi ,  Zhen-Wei Cai ,  Jonathan Lippy ,  Maria Menichincheri ,  Michele Modugno ,  Joseph Naglich ,  Becky Penhallow ,  Heidi L Perez ,  John Sack ,  Robert J Schmidt ,  Andrew Tebben ,  Chunhong Yan ,  Liping Zhang ,  Arturo Galvani ,  Louis J Lombardo ,  Robert M Borzilleri
Affiliations
  • 1. Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA. [email protected]
PMID: 22608393 DOI: 10.1016/j.bmcl.2012.04.106
Abstract

5-Butyl-1,4-diphenyl pyrazole and 2-amino-5-chloro pyrimidine acylsulfonamides were developed as potent dual antagonists of Bcl-2 and Bcl-xL. Compounds were optimized for binding to the I88, L92, I95, and F99 pockets normally occupied by pro-apoptotic protein Bim. An X-ray crystal structure confirmed the proposed binding mode. Observation of cytochrome c release from isolated mitochondria in MV-411 cells provides further evidence of target inhibition. Compounds demonstrated submicromolar antiproliferative activity in Bcl-2/Bcl-xL dependent cell lines.