Anti-apoptotic Bcl-2

Reference work entry

Abstract

The B-cell lymphoma/leukemia 2 (BCL-2) family represents a group of proteins involved in the regulation of the intrinsic (mitochondrial) apoptotic pathway. Approximately 25 members of the BCL-2 family have been grouped into three categories based on structure and function: (1) anti- apoptotic, (2) pro-apoptotic, and (3) BH3 only proteins. This chapter will focus on a family of five anti-apoptotic proteins: (1) BCL-2, (2) BCL-xL, (3) BCL-w, (4) MCL-1, and (5) A1. The decision for a cell to undergo apoptosis is regulated by the BCL-2 family of proteins. Inhibition of anti-apoptotic BCL-2 proteins is an active area of research and represents a novel pathway in cancer therapeutics. BH3 profiling is a functional assay that measures the degree to which a cancer cell is primed to undergo apoptosis by investigating how the cells evade apoptosis by three possible mechanisms: (1) inability of activator BH3-only proteins (Bim/Bid) to function, (2) loss of pro-apoptotic BCL-2 proteins (Bax/Bak), and (3) sequestration of activator BH3 proteins by anti-apoptotic BCL-2 proteins. Approaches to target BCL-2 include RNA antisense molecules (oblimersen, SPC2996); small-molecule inhibitors (venetoclax, obatoclax, ABT-737, navitoclax, AT-101); and stabilized alpha helix of BCL-2 (SAHB) peptides. These compounds are under various stages of clinical investigation in both solid and hematologic malignancies, both as single agents and in combination with other cytotoxic regimens

Keywords

Anti-apoptotic BCL-2 proteins Apoptosis Augmerosen B-cell lymphoma/leukemia 2 (BCL-2) BH3 profiling BHS mimetics A1 ABT-199 ABT-737 AT-101 BCL-w BCL-xL Gossypol derivatives Maritoclax Mcl-1 Mitochondrial outer membrane permeabilization (MOMP) Navitoclax Obatoclax mesylate Oblimersen sodium Programmed cell death SPC2996 Stabilized alpha helix of BCL-2 domains TW37 BCL-w protein Genasense® Inhibition of anti-apoptotic BCL-2 proteins Sabutoclax Stabilized alpha helix of BCL-2 domains (SAHBs) Venetoclax 

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.New York Presbyterian Hospital/Columbia CampusColumbia University Medical CenterNew YorkUSA
  2. 2.Office of Hematology and Oncology Products (OHOP)U.S. Food and Drug AdministrationSilver SpringUSA

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