Small molecule inhibition of the Bcl-X(L)-BH3 protein-protein interaction: proof-of-concept of an in vivo chemopotentiator ABT-737

Abstract

The Bcl-2 family of anti-apoptotic proteins are key regulators of programmed cell death. Bcl-2 and its closely related Bcl-X(L) counterpart are one of several pro-survival proteins which can share up to four highly conserved domains known as the BH1, BH2, BH3 and BH4 domains. These domains form the basis of a well defined groove whereupon a heterodimeric protein-protein interaction can occur with pro-apoptotic BH3 proteins such as Bad, Bid and Bim. Extensive evidence clearly indicates a strong correlation between neoplastic progression and deregulation of apoptotic pathways. Overexpression of Bcl-X(L) is associated with tumor progression, poor prognosis and resistance to chemotherapy. Antagonism of Bcl-X(L) is therefore viewed as a means to mimic the endogenous apoptotic pathways initiated by Bad, Bid and other pro-apoptotic proteins. Several successful approaches to block the Bcl-X(L)-BH3 binding groove have been reported but only recently have proteomimetics been found which could prove to be clinically useful as new anticancer agents capable of overcoming apoptosis resistance. ABT-737 is an example of one of the first small-molecule inhibitors of Bcl-2/X(L) proteins shown to be efficacious in vivo, causing complete regression in small-cell lung carcinoma tumour xenografts in mice. This review will focus on the recent advances surrounding the non-peptidic Bcl-2/X(L) inhibitor ABT-737 developed by Abbot laboratories and highlight the key structural characteristics found within this unique BH3 alpha-helical mimetic.