title: Expanding the Cancer Arsenal with Targeted Therapies: Disarmament of the Antiapoptotic Bcl-2 Proteins by Small Molecules.
abstract: A hallmark of cancer is the evasion of apoptosis, which is often associated with the upregulation of the antiapoptotic members of the Bcl-2 family of proteins. The prosurvival function of the antiapoptotic Bcl-2 proteins is manifested by capturing and neutralizing the proapoptotic Bcl-2 proteins via their BH3 death domains. Accordingly, strategies to antagonize the antiapoptotic Bcl-2 proteins have largely focused on the development of low-molecular-weight, synthetic BH3 mimetics ("magic bullets") to disrupt the protein-protein interactions between anti- and proapoptotic Bcl-2 proteins. In this way, apoptosis has been reactivated in malignant cells. Moreover, several such Bcl-2 family inhibitors are presently being evaluated for a range of cancers in clinical trials and show great promise as new additions to the cancer armamentarium. Indeed, the selective Bcl-2 inhibitor venetoclax (Venclexta) recently received FDA approval for the treatment of a specific subset of patients with chronic lymphocytic leukemia. This review focuses on the major developments in the field of Bcl-2 inhibitors over the past decade, with particular emphasis on binding modes and, thus, the origins of selectivity for specific Bcl-2 family members.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , 20 N. Pine Street, Baltimore, Maryland 21201, United States.
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Yap
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , 20 N. Pine Street, Baltimore, Maryland 21201, United States.
authors.forename: Lijia
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , 20 N. Pine Street, Baltimore, Maryland 21201, United States.
authors.forename: Maryanna E
authors.initials: ME
authors.lastname: Lanning
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy , 20 N. Pine Street, Baltimore, Maryland 21201, United States.|University of Maryland Greenebaum Cancer Center , Baltimore, Maryland 21201, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Fletcher
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D054852:Small Molecule Libraries