title: Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR.
abstract: The Bcl-2 family of proteins plays a major role in the regulation of apoptosis, or programmed cell death. Overexpression of the anti-apoptotic members of this family (Bcl-2, Bcl-x(L), and Mcl-1) can render cancer cells resistant to chemotherapeutic agents and therefore these proteins are important targets for the development of new anti-cancer agents. Here we describe the discovery of a potent, highly selective, Bcl-2 inhibitor using SAR by NMR and structure-based drug design which could serve as a starting point for the development of a Bcl-2 selective anti-cancer agent. Such an agent would potentially overcome the Bcl-x(L) mediated thrombocytopenia observed with ABT-263.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, United States.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Petros
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Huth
authors.forename: Thorsten
authors.initials: T
authors.lastname: Oost
authors.forename: Cheol-Min
authors.initials: CM
authors.lastname: Park
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
authors.forename: Xilu
authors.initials: X
authors.lastname: Wang
authors.forename: Haichao
authors.initials: H
authors.lastname: Zhang
authors.forename: Paul
authors.initials: P
authors.lastname: Nimmer
authors.forename: Renaldo
authors.initials: R
authors.lastname: Mendoza
authors.forename: Chaohong
authors.initials: C
authors.lastname: Sun
authors.forename: Jamey
authors.initials: J
authors.lastname: Mack
authors.forename: Karl
authors.initials: K
authors.lastname: Walter
authors.forename: Sarah
authors.initials: S
authors.lastname: Dorwin
authors.forename: Emily
authors.initials: E
authors.lastname: Gramling
authors.forename: Uri
authors.initials: U
authors.lastname: Ladror
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Steven W
authors.initials: SW
authors.lastname: Elmore
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Fesik
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Hajduk
mesh_terms: D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008958:Models, Molecular; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2