Exploiting BH3 mimetics for cancer therapy

Abstract

In apoptotic cells, the transcriptional induction or posttranslational activation of Bcl-2-homolgy domain-3 (BH3)-only proteins triggers the activation of the pro-apoptotic pore-forming proteins Bax and Bak. All members of this subgroup of the Bcl-2 family share a nine amino acid BH3-domain which binds to a hydrophobic groove of anti-apoptotic Bcl-2 family members that comprises residues of their BH1, BH2 and BH3 domains. These observations led to the development of BH3 mimetics, a class of small-molecule inhibitors targeting the BH3-binding domain of the pro-survival Bcl-2 family members, thereby facilitating/activating Bax/Bak-dependent apoptosis. In addition, BH3 mimetics can displace the pro-autophagic BH3only protein Beclin-1 from a complex with pro-survival Bcl-2 family members to induce autophagy. BH3 mimetics hold great promise for the treatment of cancer and currently, a large variety of natural and synthetic BH3 mimetics are characterized in preclinical studies and developed in clinical studies in an aim to exploit their therapeutic potential for the treatment of cancer.