2. Academic Validation
  3. Tegavivint triggers TECR-dependent nonapoptotic cancer cell death

Tegavivint triggers TECR-dependent nonapoptotic cancer cell death

  • Nat Chem Biol. 2025 May 26. doi: 10.1038/s41589-025-01913-4.
Logan Leak 1,  Ziwei Wang 2,  Alby J Joseph 1,  Brianna Johnson 1,  Alyssa A Chan 1,  Cassandra M Decosto 1,  Leslie Magtanong 1,  Pin-Joe Ko 1,  Weaverly Colleen Lee 1,  Joan Ritho 1,  Sophia Manukian 1,  Alec Millner 3,  Shweta Chitkara 3,  Jennifer J Salinas 4,  Rachid Skouta 5 6,  Matthew G Rees 7,  Melissa M Ronan 7,  Jennifer A Roth 7,  Chad L Myers 8,  Jason Moffat 9 10,  Charles Boone 10 11 12,  Steven J Bensinger 13 14,  David A Nathanson 4 15,  G Ekin Atilla-Gokcumen 3,  Everett J Moding 2,  Scott J Dixon 16
Affiliations

Affiliations

  • 1 Department of Biology, Stanford University, Stanford, CA, USA.
  • 2 Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.
  • 3 Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY, USA.
  • 4 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
  • 5 Department of Chemistry, University of Massachusetts, Amherst, Amherst, MA, USA.
  • 6 Department of Biology, University of Massachusetts, Amherst, Amherst, MA, USA.
  • 7 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 8 Department of Computer Science and Engineering, Bioinformatics and Computational Biology Graduate Program, University of Minnesota-Twin Cities, Minneapolis, MN, USA.
  • 9 Program in Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 10 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • 11 Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
  • 12 RIKEN Center for Sustainable Resource Science, Saitama, Japan.
  • 13 Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
  • 14 UCLA Lipidomics Laboratory, University of California, Los Angeles, Los Angeles, CA, USA.
  • 15 Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • 16 Department of Biology, Stanford University, Stanford, CA, USA. sjdixon@stanford.edu.
PMID: 40419770 DOI: 10.1038/s41589-025-01913-4
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.

Figures
Products