2. Academic Validation
  3. Small-molecule Bax agonists for cancer therapy

Small-molecule Bax agonists for cancer therapy

  • Nat Commun. 2014 Sep 17;5:4935. doi: 10.1038/ncomms5935.
Meiguo Xin 1,  Rui Li 2,  Maohua Xie 2,  Dongkyoo Park 2,  Taofeek K Owonikoko 3,  Gabriel L Sica 4,  Patrick E Corsino 5,  Jia Zhou 6,  Chunyong Ding 6,  Mark A White 7,  Andrew T Magis 8,  Suresh S Ramalingam 3,  Walter J Curran 2,  Fadlo R Khuri 3,  Xingming Deng 9
Affiliations

Affiliations

  • 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.
  • 3 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.
  • 4 Department of Pathology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 1365C Clifton Road NE, Atlanta, Georgia 30322, USA.
  • 5 Department of Pharmacology, University of Florida, 1600 SW Archer Road, Gainesville, Florida 32610, USA.
  • 6 Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555, USA.
  • 7 Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555, USA.
  • 8 Institute for Systems Biology, 401 Terry Avenue N, Seattle, Washington 98109, USA.
  • 9 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.
PMID: 25230299 DOI: 10.1038/ncomms5935
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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