The BCL-2 family protein BAX is a central mediator of apoptosis. Overexpression of anti-apoptotic BCL-2 proteins contributes to tumor development and resistance to therapy by suppressing BAX and its activators. We report the discovery of BTSA1, a pharmacologically optimized BAX activator that binds with high affinity and specificity to the N-terminal activation site and induces conformational changes to BAX leading to BAX-mediated apoptosis. BTSA1-induced BAX activation effectively promotes apoptosis in leukemia cell lines and patient samples while sparing healthy cells. BAX expression levels and cytosolic conformation regulate sensitivity to BTSA1. BTSA1 potently suppressed human acute myeloid leukemia (AML) xenografts and increased host survival without toxicity. This study provides proof-of-concept for direct BAX activation as a treatment strategy in AML.

中文翻译：

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BTSA1对BAX的直接激活克服了急性髓细胞白血病中的抗凋亡性。

BCL-2家族蛋白BAX是细胞凋亡的主要介质。抗凋亡的BCL-2蛋白的过表达通过抑制BAX及其激活剂来促进肿瘤的发展和对治疗的抵抗力。我们报告了BTSA1的发现，BTSA1是一种药理学上最优化的BAX激活剂，与N末端激活位点具有高亲和力和特异性结合，并诱导BAX的构象变化，从而导致BAX介导的细胞凋亡。BTSA1诱导的BAX激活可有效促进白血病细胞系和患者样品中的细胞凋亡，同时保留健康细胞。BAX表达水平和胞质构象调节对BTSA1的敏感性。BTSA1有效抑制人类急性髓细胞白血病（AML）异种移植并增加宿主存活率而无毒性。