Small molecule inhibitors of Bcl-2 function: modulators of apoptosis and promising anticancer agents.
Bcl-2 and related proteins play a central role in the regulation of programmed cell death or apoptosis implicated in many human diseases. As such, they have been prime targets for both basic research to understand the fundamental principles underlying the life and death of a cell, and for drug discovery, to develop a new generation of therapeutics for the treatment of cancer. Structure-function studies of the Bcl-2 family of proteins have revealed a surface pocket on anti-apoptotic Bcl-2 and Bcl-xL that is critical for their interaction with other pro-apoptotic proteins and their ability to suppress cell death signals. Intensive efforts have been made by industry to find small molecules that recognize this surface pocket of Bcl-2 or Bcl-xL and antagonize their biological functions. This article reviews the recent progress in the study of peptides, and non-peptidic natural and synthetic compounds that block the antiapoptotic function of Bcl-2 or Bcl-xL. The design and discovery of these agents has opened new avenues in the basic research of Bcl-2- regulated apoptotic processes and the development of new anticancer drugs.
Huang
Z
Z
Department of Biochemistry, University of Illinois, Urbana, IL 61801, USA. z-huang@uivc.edu