Small Molecule Inhibition of the Bcl-XL-BH3 Protein-Protein Interaction: Proof-of-Concept of an In Vivo Chemopotentiator ABT-737
Shaun R. Stauffer
Affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, WP14-3 P.O. Box 4, West Point,PA 19486 USA.
Keywords: Protein protein interactions, ABT-737, apoptosis, Bcl-XL
The Bcl-2 family of anti-apoptotic proteins are key regulators of programmed cell death. Bcl-2 and its closely related Bcl-XL 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-XL is associated with tumor progression, poor prognosis and resistance to chemotherapy. Antagonism of Bcl-XL 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-XL-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/XL 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/XL inhibitor ABT-737 developed by Abbot laboratories and highlight the key structural characteristics found within this unique BH3 alpha-helical mimetic.
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