Tegavivint triggers TECR-dependent nonapoptotic cancer cell death

IF 12.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Nature chemical biology Pub Date : 2025-05-26 DOI:10.1038/s41589-025-01913-4

Logan Leak, Ziwei Wang, Alby J. Joseph, Brianna Johnson, Alyssa A. Chan, Cassandra M. Decosto, Leslie Magtanong, Pin-Joe Ko, Weaverly Colleen Lee, Joan Ritho, Sophia Manukian, Alec Millner, Shweta Chitkara, Jennifer J. Salinas, Rachid Skouta, Matthew G. Rees, Melissa M. Ronan, Jennifer A. Roth, Chad L. Myers, Jason Moffat, Charles Boone, Steven J. Bensinger, David A. Nathanson, G. Ekin Atilla-Gokcumen, Everett J. Moding, Scott J. Dixon

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Abstract

Small molecules that induce nonapoptotic cell death are of fundamental mechanistic interest and may be useful to treat certain cancers. Here we report that tegavivint, a drug candidate undergoing human clinical trials, can activate a unique mechanism of nonapoptotic cell death in sarcomas and other cancer cells. This lethal mechanism is distinct from ferroptosis, necroptosis and pyroptosis and requires the lipid metabolic enzyme trans-2,3-enoyl-CoA reductase (TECR). TECR is canonically involved in the synthesis of very-long-chain fatty acids but appears to promote nonapoptotic cell death in response to CIL56 and tegavivint via the synthesis of the saturated long-chain fatty acid palmitate. These findings outline a lipid-dependent nonapoptotic cell death mechanism that can be induced by a drug candidate currently being tested in humans.

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替加维文特触发tecr依赖性非凋亡癌细胞死亡

诱导非凋亡细胞死亡的小分子具有重要的机制意义，可能对治疗某些癌症有用。在这里，我们报道了一种正在进行人体临床试验的候选药物替加维文特，可以激活肉瘤和其他癌细胞的非凋亡细胞死亡的独特机制。这种致死机制不同于铁下垂、坏死性下垂和焦下垂，需要脂质代谢酶反式-2,3-烯酰辅酶a还原酶（TECR）。TECR通常参与长链脂肪酸的合成，但似乎通过饱和长链脂肪酸棕榈酸酯的合成促进非凋亡性细胞死亡，以响应CIL56和替加维文特。这些发现概述了一种脂质依赖性非凋亡细胞死亡机制，这种机制可以由一种目前正在人体试验的候选药物诱导。

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来源期刊

Nature chemical biology 生物-生化与分子生物学

CiteScore

23.90

自引率

1.40%

发文量

238

审稿时长

12 months

期刊介绍： Nature Chemical Biology stands as an esteemed international monthly journal, offering a prominent platform for the chemical biology community to showcase top-tier original research and commentary. Operating at the crossroads of chemistry, biology, and related disciplines, chemical biology utilizes scientific ideas and approaches to comprehend and manipulate biological systems with molecular precision. The journal embraces contributions from the growing community of chemical biologists, encompassing insights from chemists applying principles and tools to biological inquiries and biologists striving to comprehend and control molecular-level biological processes. We prioritize studies unveiling significant conceptual or practical advancements in areas where chemistry and biology intersect, emphasizing basic research, especially those reporting novel chemical or biological tools and offering profound molecular-level insights into underlying biological mechanisms. Nature Chemical Biology also welcomes manuscripts describing applied molecular studies at the chemistry-biology interface due to the broad utility of chemical biology approaches in manipulating or engineering biological systems. Irrespective of scientific focus, we actively seek submissions that creatively blend chemistry and biology, particularly those providing substantial conceptual or methodological breakthroughs with the potential to open innovative research avenues. The journal maintains a robust and impartial review process, emphasizing thorough chemical and biological characterization.