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Biomap#26

Title: List of Bcl2 inhibitors
 
Legend: Bcl-2 is the founding member of a protein family composed of pro- and anti-apoptotic molecules that serve as an essential control point in apoptosis. The Bcl-2 family is defined by the presence of up to four conserved Bcl-2 homology (BH) domains, all of which include alpha-helical segments. Anti-apoptotic proteins (for example, Bcl-2 and Bcl-XL) display sequence conservation in all BH domains, whereas pro-apoptotic proteins are divided into multidomain members (e.g. Bax and Bak), and BH3-only members (e.g. Bid and Bad) that display sequence similarity only to the BH3 alpha-helical domain. The amphipathic alpha-helical BH3 segment of pro-apoptotic family members is a required death domain that binds to the hydrophobic groove formed by the juxtaposition of BH1, BH2, and BH3 domains of anti-apoptotic multidomain members. In response to apoptotic stimuli, BH3-only proteins activate pro-apoptotic multidomain proteins promoting their assembly into pores, which ultimately leads to mitochondrial membrane permeabilization and thus initiates the intrinsic apoptotic pathway. Among Bcl-2 inhibitors under development (e.g. antimycin-A, ABT-737, BH3I-1, BH3I-2, chelerythrine, gossypol, HA14-1, obatoclax [GX15-070], oblimersen [Genasense], sanguinarine, streptorubin-B, ABT-263), most are small molecules acting as BH3 mimetics. REFERENCES: [1] Adams JM et al, Oncogene 2007, 26:1324-37. [2] Manion MK et al, Curr Opin Invest Drugs 2006, 7:1077-84
Author: The MMMP Team (updated: Nov 2007)

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