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

Dulguun Amgalan, Thomas P. Garner, Ryan Pekson, Xiaotong F. Jia, Mounica Yanamandala, Victor Paulino, Felix G. Liang, J. Jose Corbalan, Jaehoon Lee, Yun Chen, George S. Karagiannis, Luis Rivera Sanchez, Huizhi Liang, Swathi Rao Narayanagari, Kelly Mitchell, Andrea Lopez, Victoria Margulets, Marco Scarlata, Gaetano Santulli, Aarti AsnaniRandall T. Peterson, Rachel B. Hazan, John S. Condeelis, Maja H. Oktay, Ulrich Steidl, Lorrie A. Kirshenbaum, Evripidis Gavathiotis, Richard N. Kitsis

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)315-328
Number of pages14
JournalNature Cancer
Volume1
Issue number3
DOIs
StatePublished - Mar 1 2020

ASJC Scopus subject areas

  • Medicine(all)

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