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 White, Andrew T. Magis, Suresh S. Ramalingam, Walter J. Curran, Fadlo R. Khuri, Xingming Deng

Research output: Contribution to journalArticle

66 Citations (Scopus)

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 languageEnglish (US)
Article number4935
JournalNature Communications
Volume5
DOIs
StatePublished - 2015

Fingerprint

apoptosis
lungs
Serine
therapy
cancer
Apoptosis
Molecules
Lung Neoplasms
Small Molecule Libraries
molecules
Neoplasms
phosphorylation
Phosphorylation
cytochromes
regulators
Mitochondrial Membranes
Cytochromes c
oligomers
Oligomers
death

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Xin, M., Li, R., Xie, M., Park, D., Owonikoko, T. K., Sica, G. L., ... Deng, X. (2015). Small-molecule Bax agonists for cancer therapy. Nature Communications, 5, [4935]. https://doi.org/10.1038/ncomms5935

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; Magis, Andrew T.; Ramalingam, Suresh S.; Curran, Walter J.; Khuri, Fadlo R.; Deng, Xingming.

In: Nature Communications, Vol. 5, 4935, 2015.

Research output: Contribution to journalArticle

Xin, M, Li, R, Xie, M, Park, D, Owonikoko, TK, Sica, GL, Corsino, PE, Zhou, J, Ding, C, White, M, Magis, AT, Ramalingam, SS, Curran, WJ, Khuri, FR & Deng, X 2015, 'Small-molecule Bax agonists for cancer therapy', Nature Communications, vol. 5, 4935. https://doi.org/10.1038/ncomms5935
Xin M, Li R, Xie M, Park D, Owonikoko TK, Sica GL et al. Small-molecule Bax agonists for cancer therapy. Nature Communications. 2015;5. 4935. https://doi.org/10.1038/ncomms5935
Xin, Meiguo ; Li, Rui ; Xie, Maohua ; Park, Dongkyoo ; Owonikoko, Taofeek K. ; Sica, Gabriel L. ; Corsino, Patrick E. ; Zhou, Jia ; Ding, Chunyong ; White, Mark ; Magis, Andrew T. ; Ramalingam, Suresh S. ; Curran, Walter J. ; Khuri, Fadlo R. ; Deng, Xingming. / Small-molecule Bax agonists for cancer therapy. In: Nature Communications. 2015 ; Vol. 5.
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