Small molecule inhibition of the Bcl-X(L)-BH3 protein-protein interaction: proof-of-concept of an in vivo chemopotentiator ABT-737.
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.
Stauffer
Shaun R
SR
Department of Medicinal Chemistry, Merck Research Laboratories, WP14-3 P.O. Box 4, West Point, PA 19486, USA. shaun_stauffer@merck.com
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D051379:Mice; D018716:Molecular Mimicry; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D009596:Nitrophenols / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding; D025941:Protein Interaction Mapping; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics
C501332:ABT-737; D000970:Antineoplastic Agents; D051023:BH3 Interacting Domain Death Agonist Protein; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D051020:bcl-X Protein