title: Structure-based discovery of a new class of Bcl-xL antagonists.
abstract: Apoptosis, or programmed cell death, plays a key role in normal tissue homeostasis ensuring a proper balance between cell production and cell loss. Anti-apoptotic Bcl-2-family proteins are central regulators of the apoptotic pathway and due to their ability to confer tumor resistance to chemotherapy or radiation, have been recently validated as targets for cancer drug discovery. Since the crucial interaction between pro- and anti-apoptotic members occurs via a conserved region located on the surface of the protein, a viable way to inhibit the anti-death activity of Bcl-2 proteins is to design small molecule inhibitors that occupy this cavity. Here, we describe a structure-based approach that led to the identification of four small molecule inhibitors directed at the hydrophobic groove on the surface of the Bcl-2 family protein Bcl-xL. The compounds were characterized in a number of assays including in vitro binding using 15N-labeled protein, a displacement DELFIA assay, and a cell-based viability assay with human cancer cells.
authors.affiliation: Burnham Institute for Medical Research, Cancer Center and Infectious and Inflammatory Disease Center, La Jolla, CA 92037, USA.
authors.forename: Michele F
authors.initials: MF
authors.lastname: Rega
authors.forename: Marilisa
authors.initials: M
authors.lastname: Leone
authors.forename: Dawoon
authors.initials: D
authors.lastname: Jung
authors.forename: Naomi J H
authors.initials: NJ
authors.lastname: Cotton
authors.forename: John L
authors.initials: JL
authors.lastname: Stebbins
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017124:Conserved Sequence; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007118:Immunoassay; D011485:Protein Binding; D013329:Structure-Activity Relationship; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D051020:bcl-X Protein