A small-molecule allosteric inhibitor of BAX protects against doxorubicin-induced cardiomyopathy
A small-molecule allosteric inhibitor of BAX protects against doxorubicin-induced cardiomyopathy
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DOI：
10.1038/s43018-020-0039-1
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发表时间：
2020-03-01
期刊：
影响因子：
22.7
通讯作者：
Kitsis, Richard N.
中科院分区：
文献类型：
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作者：
Amgalan, Dulguun;Garner, Thomas P.;Kitsis, Richard N.
阿霉素仍然是许多癌症方案的基本成分，但它的使用受到致死性心肌病的限制，由于多效性机制导致心肌细胞凋亡和坏死性死亡，这种疾病一直很难靶向。在这里，我们证明了Bax在阿霉素诱导的心肌病中是限速的，并发现了一种小分子Bax抑制剂，可以阻断细胞凋亡和坏死来预防这种综合征。通过变构抑制Bax构象激活，该化合物阻止Bax易位到线粒体，从而消除这两种形式的细胞死亡。当与阿霉素联合使用时，这种Bax抑制剂可以预防斑马鱼和小鼠的心肌病。值得注意的是，心脏保护不会影响阿霉素在体内减少白血病或乳腺癌负担的有效性，这主要是因为线粒体死亡机制的启动增加和癌细胞中Bax水平的提高。本研究确定Bax是阿霉素引起的心肌病的一个可操作的靶点，并提供了一个小分子治疗的原型。
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.