Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR.
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.
Petros
Andrew M
AM
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, United States.
Huth
Jeffrey R
JR
Oost
Thorsten
T
Park
Cheol-Min
CM
Ding
Hong
H
Wang
Xilu
X
Zhang
Haichao
H
Nimmer
Paul
P
Mendoza
Renaldo
R
Sun
Chaohong
C
Mack
Jamey
J
Walter
Karl
K
Dorwin
Sarah
S
Gramling
Emily
E
Ladror
Uri
U
Rosenberg
Saul H
SH
Elmore
Steven W
SW
Fesik
Stephen W
SW
Hajduk
Philip J
PJ
D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008958:Models, Molecular; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D019253:Proto-Oncogene Proteins c-bcl-2