Bcl-2 family proteins as targets for anticancer drug design

Bcl-2 family proteins are key regulators of programmed cell death or apopto sis that is implicated in many human diseases, particularly cancer. In rece nt years, they have attracted intensive interest in both basic research to understand the fundamental principles of cell survival and cell death and d rug discovery to develop a new class of anticancer agents. The Bcl-2 family includes both anti-and pro-apoptotic proteins with opposing biological fun ctions in either inhibiting or promoting cell death. High expression of ant i-apoptotic members such as Bcl-2 and Bcl-x(L) commonly found in human canc ers contributes to neoplastic cell expansion and interferes with the therap eutic action of many chemotherapeutic drugs. The functional blockade of Bcl -2 or Bcl-x(L) could either restore the apoptotic process in tumor cells or sensitize these tumors for chemo- and radiotherapies. This article reviews the recent progress in the design and discovery of small molecules that bl ock the anti-apoptotic function of Bcl-2 or Bcl-x(L). These chemical inhibi tors are effective modulators of apoptosis and promising leads for the furt her development of new anticancer agents.