2. Academic Validation
  3. Pyrazole and pyrimidine phenylacylsulfonamides as dual Bcl-2/Bcl-xL antagonists

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

Affiliation

  • 1 Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA. gretchen.schroeder@bms.com
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.

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