Gretchen M Schroeder,
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
[show abstract]
[hide abstract]
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.
Bioorganic & medicinal chemistry letters 04/2012; 22(12):3951-6. · 2.65 Impact Factor
