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; Xingming Deng

doi:10.1038/ncomms5935

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, Xingming Deng

Research output: Contribution to journal › Article › peer-review

118 Scopus citations

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.

Original language	English (US)
Article number	4935
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5935
State	Published - 2014

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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@article{68f90188ec584bd58972feeb83c19ad7,

title = "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.",

author = "Meiguo Xin and Rui Li and Maohua Xie and Dongkyoo Park and Owonikoko, {Taofeek K.} and Sica, {Gabriel L.} and Corsino, {Patrick E.} and Jia Zhou and Chunyong Ding and White, {Mark A.} and Magis, {Andrew T.} and Ramalingam, {Suresh S.} and Curran, {Walter J.} and Khuri, {Fadlo R.} and Xingming Deng",

note = "Funding Information: This work was supported by NCI, National Institutes of Health grant R01CA136534, by Winship Inaugural Kennedy Seed Grant and by Flight Attendant Medical Research Institute Clinical Innovator Award. Molecular graphics and analyses were performed with the UCSF Chimera package, which is developed by the Resource for Biocomputing, Visualization and Informatics at the University of California, San Francisco (supported by NIGMS P41-GM103311). We thank Anthea Hammond for editing the manuscript.",

year = "2014",

doi = "10.1038/ncomms5935",

language = "English (US)",

volume = "5",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - Small-molecule Bax agonists for cancer therapy

AU - Xin, Meiguo

AU - Li, Rui

AU - Xie, Maohua

AU - Park, Dongkyoo

AU - Owonikoko, Taofeek K.

AU - Sica, Gabriel L.

AU - Corsino, Patrick E.

AU - Zhou, Jia

AU - Ding, Chunyong

AU - White, Mark A.

AU - Magis, Andrew T.

AU - Ramalingam, Suresh S.

AU - Curran, Walter J.

AU - Khuri, Fadlo R.

AU - Deng, Xingming

N1 - Funding Information: This work was supported by NCI, National Institutes of Health grant R01CA136534, by Winship Inaugural Kennedy Seed Grant and by Flight Attendant Medical Research Institute Clinical Innovator Award. Molecular graphics and analyses were performed with the UCSF Chimera package, which is developed by the Resource for Biocomputing, Visualization and Informatics at the University of California, San Francisco (supported by NIGMS P41-GM103311). We thank Anthea Hammond for editing the manuscript.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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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Small-molecule Bax agonists for cancer therapy

Abstract

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