title: Small-molecule Bax agonists for cancer therapy.
abstract: Bax, a central death regulator, is required at the decisional stage of apoptosis. We recently identified serine 184 (S184) of Bax as a critical functional switch controlling its proapoptotic activity. Here we used the structural pocket around S184 as a docking site to screen the NCI library of small molecules using the UCSF-DOCK programme suite. Three compounds, small-molecule Bax agonists SMBA1, SMBA2 and SMBA3, induce conformational changes in Bax by blocking S184 phosphorylation, facilitating Bax insertion into mitochondrial membranes and forming Bax oligomers. The latter leads to cytochrome c release and apoptosis in human lung cancer cells, which occurs in a Bax- but not Bak-dependent fashion. SMBA1 potently suppresses lung tumour growth via apoptosis by selectively activating Bax in vivo without significant normal tissue toxicity. Development of Bax agonists as a new class of anticancer drugs offers a strategy for the treatment of lung cancer and other Bax-expressing malignancies.
authors.affiliation: Department of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32610, USA.
authors.forename: Meiguo
authors.initials: M
authors.lastname: Xin
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 1365C Clifton Road NE, Atlanta, Georgia 30322, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 1365C Clifton Road NE, Atlanta, Georgia 30322, USA.
authors.forename: Maohua
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 1365C Clifton Road NE, Atlanta, Georgia 30322, USA.
authors.forename: Dongkyoo
authors.initials: D
authors.lastname: Park
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 1365C Clifton Road NE, Atlanta, Georgia 30322, USA.
authors.forename: Taofeek K
authors.initials: TK
authors.lastname: Owonikoko
authors.affiliation: Department of Pathology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 1365C Clifton Road NE, Atlanta, Georgia 30322, USA.
authors.forename: Gabriel L
authors.initials: GL
authors.lastname: Sica
authors.affiliation: Department of Pharmacology, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32610, USA.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Corsino
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555, USA.
authors.forename: Chunyong
authors.initials: C
authors.lastname: Ding
authors.affiliation: Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: White
authors.affiliation: Institute for Systems Biology, 401 Terry Avenue N, Seattle, Washington 98109, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Magis
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 1365C Clifton Road NE, Atlanta, Georgia 30322, USA.
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 1365C Clifton Road NE, Atlanta, Georgia 30322, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Curran
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 1365C Clifton Road NE, Atlanta, Georgia 30322, USA.
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.affiliation: 1] Department of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32610, USA [2] Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 1365C Clifton Road NE, Atlanta, Georgia 30322, USA.
authors.forename: Xingming
authors.initials: X
authors.lastname: Deng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D017209:Apoptosis; D001665:Binding Sites; D002460:Cell Line; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy*; D010766:Phosphorylation; D055503:Protein Multimerization; D012694:Serine / Q000737:chemistry; D051028:bcl-2-Associated X Protein / Q000819:agonists* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; D051028:bcl-2-Associated X Protein; D012694:Serine