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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.

SUBMITTER: Xin M

PROVIDER: S-EPMC4172359 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Small-molecule Bax agonists for cancer therapy.

Xin Meiguo M Li Rui R Xie Maohua M Park Dongkyoo D Owonikoko Taofeek K TK Sica Gabriel L GL Corsino Patrick E PE Zhou Jia J Ding Chunyong C White Mark A MA Magis Andrew T AT Ramalingam Suresh S SS Curran Walter J WJ Khuri Fadlo R FR Deng Xingming X

Nature communications 20140917

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 ...[more]

PMID: 25230299

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Small-molecule Bax agonists for cancer therapy.

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Small-molecule Bax agonists for cancer therapy.

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