title: BH4 domain of Bcl-2 as a novel target for cancer therapy.
abstract: Overexpression of B cell lymphoma 2 (Bcl-2) proteins is associated with therapy resistance in various human cancers. Traditional approaches target the Bcl-2 homology (BH)3 domain of Bcl-2; however, the BH4 domain represents a superior therapeutic target in light of its unique structure and crucial involvement in many cellular functions. In this critical review, we focus on the structural and functional basis of targeting the BH4 domain of Bcl-2, and highlight the recent advances in drug discovery efforts toward small-molecule BH4 domain inhibitors (e.g. BDA-366). The proof-of-concept studies support the hypothesis that targeting the BH4 domain of Bcl-2 holds promise to offer a novel anticancer therapy through the induction of apoptosis and an increased potential to overcome therapeutic resistance.
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Wild
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Ye
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Haiying
authors.initials: H
authors.lastname: Chen
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Wold
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address: jizhou@utmb.edu.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004983:Ethanolamines / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D000072417:Protein Domains; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; C000610367:BDA-366; D004983:Ethanolamines; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2