Direct and selective small-molecule activation of proapoptotic BAX

Evripidis Gavathiotis, Denis E. Reyna, Joseph A. Bellairs, Elizaveta S. Leshchiner, Loren D. Walensky

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)639-645
Number of pages7
JournalNature Chemical Biology
Volume8
Issue number7
DOIs
StatePublished - Jul 2012

Fingerprint

Apoptosis
Proteins
Cell Survival
Cell Death
Neoplasms
Death Domain

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Gavathiotis, E., Reyna, D. E., Bellairs, J. A., Leshchiner, E. S., & Walensky, L. D. (2012). Direct and selective small-molecule activation of proapoptotic BAX. Nature Chemical Biology, 8(7), 639-645. https://doi.org/10.1038/nchembio.995

Direct and selective small-molecule activation of proapoptotic BAX. / Gavathiotis, Evripidis; Reyna, Denis E.; Bellairs, Joseph A.; Leshchiner, Elizaveta S.; Walensky, Loren D.

In: Nature Chemical Biology, Vol. 8, No. 7, 07.2012, p. 639-645.

Research output: Contribution to journalArticle

Gavathiotis, E, Reyna, DE, Bellairs, JA, Leshchiner, ES & Walensky, LD 2012, 'Direct and selective small-molecule activation of proapoptotic BAX', Nature Chemical Biology, vol. 8, no. 7, pp. 639-645. https://doi.org/10.1038/nchembio.995
Gavathiotis, Evripidis ; Reyna, Denis E. ; Bellairs, Joseph A. ; Leshchiner, Elizaveta S. ; Walensky, Loren D. / Direct and selective small-molecule activation of proapoptotic BAX. In: Nature Chemical Biology. 2012 ; Vol. 8, No. 7. pp. 639-645.
@article{298c540c429549939aa38c6a5a12476d,
title = "Direct and selective small-molecule activation of proapoptotic BAX",
abstract = "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.",
author = "Evripidis Gavathiotis and Reyna, {Denis E.} and Bellairs, {Joseph A.} and Leshchiner, {Elizaveta S.} and Walensky, {Loren D.}",
year = "2012",
month = "7",
doi = "10.1038/nchembio.995",
language = "English (US)",
volume = "8",
pages = "639--645",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "7",

}

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=84862883409&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862883409&partnerID=8YFLogxK

U2 - 10.1038/nchembio.995

DO - 10.1038/nchembio.995

M3 - Article

VL - 8

SP - 639

EP - 645

JO - Nature Chemical Biology

JF - Nature Chemical Biology

SN - 1552-4450

IS - 7

ER -