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Small-molecule Bax agonists for cancer therapy.
Xin, Meiguo; Li, Rui; Xie, Maohua; Park, Dongkyoo; Owonikoko, Taofeek K; Sica, Gabriel L; Corsino, Patrick E; Zhou, Jia; Ding, Chunyong; White, Mark A; Magis, Andrew T; Ramalingam, Suresh S; Curran, Walter J; Khuri, Fadlo R; Deng, Xingming.
Afiliación
  • Xin M; Department of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32610, USA.
  • Li R; Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 1365C Clifton Road NE, Atlanta, Georgia 30322, USA.
  • Xie M; Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 1365C Clifton Road NE, Atlanta, Georgia 30322, USA.
  • Park D; Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 1365C Clifton Road NE, Atlanta, Georgia 30322, USA.
  • Owonikoko TK; 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.
  • Sica GL; Department of Pathology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 1365C Clifton Road NE, Atlanta, Georgia 30322, USA.
  • Corsino PE; Department of Pharmacology, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32610, USA.
  • Zhou J; Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555, USA.
  • Ding C; Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555, USA.
  • White MA; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555, USA.
  • Magis AT; Institute for Systems Biology, 401 Terry Avenue N, Seattle, Washington 98109, USA.
  • Ramalingam SS; 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.
  • Curran WJ; Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 1365C Clifton Road NE, Atlanta, Georgia 30322, USA.
  • Khuri FR; 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.
  • Deng X; 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.
Nat Commun ; 5: 4935, 2014 Sep 17.
Article en En | MEDLINE | ID: mdl-25230299
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.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Proteína X Asociada a bcl-2 / Neoplasias Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Proteína X Asociada a bcl-2 / Neoplasias Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2014 Tipo del documento: Article País de afiliación: Estados Unidos