title: From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors.
abstract: Members of the B cell lymphoma 2 (BCL-2) gene family have a central role in regulating programmed cell death by controlling pro-apoptotic and anti-apoptotic intracellular signals. In cancer, apoptosis evasion through dysregulation of specific BCL-2 family genes is a recurring event; accordingly, selective inhibition of specific anti-apoptotic BCL-2 family proteins represents an exciting therapeutic opportunity. A combination of nuclear magnetic resonance (NMR)-based screening and structure-based drug design has yielded the first bona fide BCL-2 homology 3 (BH3) mimetics, including the BCL-2 and BCL-XLdual antagonist navitoclax, which is the first BCL-2 family inhibitor to show efficacy in patients with cancer. Clinical experience with navitoclax prompted the generation of the highly selective BCL-2 inhibitor venetoclax, which is now approved in the United States for the treatment of patients with chronic lymphocytic leukaemia with 17p deletion who have received at least one prior therapy. Recent advances have also been made in the development of potent and selective inhibitors of BCL-XLand myeloid cell leukaemia 1 (MCL1), which are additional BCL-2 family members with established anti-apoptotic roles in cancer. Here we review the latest progress in direct and selective targeting of BCL-2 family proteins for cancer therapy.
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
authors.affiliation: Genentech, 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Fairbrother
authors.affiliation: AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, USA.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Leverson
authors.affiliation: AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Souers
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D058990:Molecular Targeted Therapy / Q000379:methods*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D054730:Protein Interaction Domains and Motifs; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2