Small-molecule Bax agonists for cancer therapy

Meiguo Xin, Rui Li, Maohua Xie, Dongkyoo Park, Taofeek K. Owonikoko, Gabriel L. Sica, Patrick E. Corsino, Jia Zhou, Chunyong Ding, Mark A. White, Andrew T. Magis, Suresh S. Ramalingam, Walter J. Curran, Fadlo R. Khuri and Xingming Deng ()
Additional contact information
Meiguo Xin: University of Florida
Rui Li: Emory University School of Medicine and Winship Cancer Institute of Emory University
Maohua Xie: Emory University School of Medicine and Winship Cancer Institute of Emory University
Dongkyoo Park: Emory University School of Medicine and Winship Cancer Institute of Emory University
Taofeek K. Owonikoko: Emory University School of Medicine and Winship Cancer Institute of Emory University
Gabriel L. Sica: Emory University School of Medicine and Winship Cancer Institute of Emory University
Patrick E. Corsino: University of Florida
Jia Zhou: Chemical Biology Program, University of Texas Medical Branch
Chunyong Ding: Chemical Biology Program, University of Texas Medical Branch
Mark A. White: Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch
Andrew T. Magis: Institute for Systems Biology
Suresh S. Ramalingam: Emory University School of Medicine and Winship Cancer Institute of Emory University
Walter J. Curran: Emory University School of Medicine and Winship Cancer Institute of Emory University
Fadlo R. Khuri: Emory University School of Medicine and Winship Cancer Institute of Emory University
Xingming Deng: University of Florida

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5935

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