title: Pyrazole and pyrimidine phenylacylsulfonamides as dual Bcl-2/Bcl-xL antagonists.
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.
authors.affiliation: Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA. gretchen.schroeder@bms.com
authors.forename: Gretchen M
authors.initials: GM
authors.lastname: Schroeder
authors.forename: Donna
authors.initials: D
authors.lastname: Wei
authors.forename: Patrizia
authors.initials: P
authors.lastname: Banfi
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Cai
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lippy
authors.forename: Maria
authors.initials: M
authors.lastname: Menichincheri
authors.forename: Michele
authors.initials: M
authors.lastname: Modugno
authors.forename: Joseph
authors.initials: J
authors.lastname: Naglich
authors.forename: Becky
authors.initials: B
authors.lastname: Penhallow
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Perez
authors.forename: John
authors.initials: J
authors.lastname: Sack
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schmidt
authors.forename: Andrew
authors.initials: A
authors.lastname: Tebben
authors.forename: Chunhong
authors.initials: C
authors.lastname: Yan
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.forename: Arturo
authors.initials: A
authors.lastname: Galvani
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
authors.forename: Robert M
authors.initials: RM
authors.lastname: Borzilleri
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D045304:Cytochromes c