TY - JOUR
T1 - Direct and selective small-molecule activation of proapoptotic BAX
AU - Gavathiotis, Evripidis
AU - Reyna, Denis E.
AU - Bellairs, Joseph A.
AU - Leshchiner, Elizaveta S.
AU - Walensky, Loren D.
N1 - Funding Information:
We thank E. Smith for editorial and graphics assistance, M. Davis for help with establishing the competitive BAX binding assay, G. Bird for BIM SAHB production and characterization and CreaGen Biosciences for BAM7 resynthesis and characterization. This research program was supported by a grant from the William Lawrence and Blanche Hughes Foundation to L.D.W. Additional funding was provided by US National Institutes of Health (NIH) grant 4R00HL095929 to E.G. and NIH grant 5R01CA050239 and a Stand Up to Cancer Innovative Research Grant to L.D.W.
PY - 2012/7
Y1 - 2012/7
N2 - BCL-2 family proteins are key regulators of the apoptotic pathway. Antiapoptotic members sequester the BCL-2 homology 3 (BH3) death domains of proapoptotic members such as BAX to maintain cell survival. The antiapoptotic BH3-binding groove has been successfully targeted to reactivate apoptosis in cancer. We recently identified a geographically distinct BH3-binding groove that mediates direct BAX activation, suggesting a new strategy for inducing apoptosis by flipping BAX's 'on switch'. Here we applied computational screening to identify a BAX activator molecule that directly and selectively activates BAX. We demonstrate by NMR and biochemical analyses that the molecule engages the BAX trigger site and promotes the functional oligomerization of BAX. The molecule does not interact with the BH3-binding pocket of antiapoptotic proteins or proapoptotic BAK and induces cell death in a BAX-dependent fashion. To our knowledge, we report the first gain-of-function molecular modulator of a BCL-2 family protein and demonstrate a new paradigm for pharmacologic induction of apoptosis.
AB - BCL-2 family proteins are key regulators of the apoptotic pathway. Antiapoptotic members sequester the BCL-2 homology 3 (BH3) death domains of proapoptotic members such as BAX to maintain cell survival. The antiapoptotic BH3-binding groove has been successfully targeted to reactivate apoptosis in cancer. We recently identified a geographically distinct BH3-binding groove that mediates direct BAX activation, suggesting a new strategy for inducing apoptosis by flipping BAX's 'on switch'. Here we applied computational screening to identify a BAX activator molecule that directly and selectively activates BAX. We demonstrate by NMR and biochemical analyses that the molecule engages the BAX trigger site and promotes the functional oligomerization of BAX. The molecule does not interact with the BH3-binding pocket of antiapoptotic proteins or proapoptotic BAK and induces cell death in a BAX-dependent fashion. To our knowledge, we report the first gain-of-function molecular modulator of a BCL-2 family protein and demonstrate a new paradigm for pharmacologic induction of apoptosis.
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U2 - 10.1038/nchembio.995
DO - 10.1038/nchembio.995
M3 - Article
C2 - 22634637
AN - SCOPUS:84862883409
SN - 1552-4450
VL - 8
SP - 639
EP - 645
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 7
ER -