Small-molecule Bax agonists for cancer therapy

M Xin, R Li, M Xie, D Park, T K Owonikoko, G L Sica, P E Corsino, J Zhou, C Ding, Mark A White, A T Magis, S S Ramalingam, W J Curran, F 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
    Pages (from-to)4935
    JournalNature Communications
    Volume5
    DOIs
    StatePublished - Sep 17 2014

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    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

    Cite this

    Xin, M., Li, R., Xie, M., Park, D., Owonikoko, T. K., Sica, G. L., ... Deng, X. (2014). 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, M; Li, R; Xie, M; Park, D; Owonikoko, T K; Sica, G L; Corsino, P E; Zhou, J; Ding, C; White, Mark A; Magis, A T; Ramalingam, S S; Curran, W J; Khuri, F R; Deng, Xingming.

    In: Nature Communications, Vol. 5, 17.09.2014, p. 4935.

    Research output: Contribution to journalArticle

    Xin, M, Li, R, Xie, M, Park, D, Owonikoko, TK, Sica, GL, Corsino, PE, Zhou, J, Ding, C, White, MA, Magis, AT, Ramalingam, SS, Curran, WJ, Khuri, FR & Deng, X 2014, 'Small-molecule Bax agonists for cancer therapy', Nature Communications, vol. 5, pp. 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. 2014 Sep 17;5:4935. https://doi.org/10.1038/ncomms5935
    Xin, M ; Li, R ; Xie, M ; Park, D ; Owonikoko, T K ; Sica, G L ; Corsino, P E ; Zhou, J ; Ding, C ; White, Mark A ; Magis, A T ; Ramalingam, S S ; Curran, W J ; Khuri, F R ; Deng, Xingming. / Small-molecule Bax agonists for cancer therapy. In: Nature Communications. 2014 ; Vol. 5. pp. 4935.
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