PUBLICATION

A small-molecule allosteric inhibitor of BAX protects against doxorubicin-induced cardiomyopathy

Authors
Amgalan, D., Garner, T.P., Pekson, R., Jia, X.F., Yanamandala, M., Paulino, V., Liang, F.G., Corbalan, J.J., Lee, J., Chen, Y., Karagiannis, G.S., Sanchez, L.R., Liang, H., Narayanagari, S.R., Mitchell, K., Lopez, A., Margulets, V., Scarlata, M., Santulli, G., Asnani, A., Peterson, R.T., Hazan, R.B., Condeelis, J.S., Oktay, M.H., Steidl, U., Kirshenbaum, L.A., Gavathiotis, E., Kitsis, R.N.
ID
ZDB-PUB-200811-7
Date
2020
Source
Nature cancer   1: 315-328 (Journal)
Registered Authors
Peterson, Randall
Keywords
none
MeSH Terms
  • Animals
  • Apoptosis/physiology
  • Cardiomyopathies*/chemically induced
  • Doxorubicin/adverse effects
  • Mice
  • Necrosis
  • Zebrafish*/metabolism
  • bcl-2-Associated X Protein
PubMed
32776015 Full text @ Nat Cancer
Abstract
Doxorubicin remains an essential component of many cancer regimens, but its use is limited by lethal cardiomyopathy, which has been difficult to target, owing to pleiotropic mechanisms leading to apoptotic and necrotic cardiac cell death. Here we show that BAX is rate-limiting in doxorubicin-induced cardiomyopathy and identify a small-molecule BAX inhibitor that blocks both apoptosis and necrosis to prevent this syndrome. By allosterically inhibiting BAX conformational activation, this compound blocks BAX translocation to mitochondria, thereby abrogating both forms of cell death. When co-administered with doxorubicin, this BAX inhibitor prevents cardiomyopathy in zebrafish and mice. Notably, cardioprotection does not compromise the efficacy of doxorubicin in reducing leukemia or breast cancer burden in vivo, primarily due to increased priming of mitochondrial death mechanisms and higher BAX levels in cancer cells. This study identifies BAX as an actionable target for doxorubicin-induced cardiomyopathy and provides a prototype small-molecule therapeutic.
Genes / Markers
Figures
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Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping