title: Small-Molecule Bcl2 BH4 Antagonist for Lung Cancer Therapy.
abstract: The BH4 domain of Bcl2 is required for its antiapoptotic function, thus constituting a promising anticancer target. We identified a small-molecule Bcl2-BH4 domain antagonist, BDA-366, that binds BH4 with high affinity and selectivity. BDA-366-Bcl2 binding induces conformational change in Bcl2 that abrogates its antiapoptotic function, converting it from a survival molecule to a cell death inducer. BDA-366 suppresses growth of lung cancer xenografts derived from cell lines and patient without significant normal tissue toxicity at effective doses. mTOR inhibition upregulates Bcl2 in lung cancer cells and tumor tissues from clinical trial patients. Combined BDA-366 and RAD001 treatment exhibits strong synergy against lung cancer in vivo. Development of this Bcl2-BH4 antagonist may provide a strategy to improve lung cancer outcome.
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
authors.forename: Bingshe
authors.initials: B
authors.lastname: Han
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
authors.forename: Dongkyoo
authors.initials: D
authors.lastname: Park
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA 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, Atlanta, GA 30322, USA.
authors.forename: Maohua
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
authors.forename: Taofeek K
authors.initials: TK
authors.lastname: Owonikoko
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
authors.forename: Guojing
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
authors.forename: Gabriel L
authors.initials: GL
authors.lastname: Sica
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Chunyong
authors.initials: C
authors.lastname: Ding
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Institute for Systems Biology, Seattle, WA 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, Atlanta, GA 30322, USA.
authors.forename: Zhuo G
authors.initials: ZG
authors.lastname: Chen
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Curran
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA. Electronic address: xdeng4@emory.edu.
authors.forename: Xingming
authors.initials: X
authors.lastname: Deng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000595707:BCL2 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D054852:Small Molecule Libraries; C052617:Bcl2 protein, mouse