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Peer-reviewedCC BY-NC-ND 4.0Nature Chemical Biology

A covalent PFKL activator suppresses tumor growth

  • Xiaoding Jiang1
  • Eric M. Lynch2
  • Congcong Lyu3
  • Crystal N. Wilson3
  • Lauren E. Salay2
  • Hayden T. Hess4
  • Scott N. Lyons3
  • Mu-Jie Lu3
  • Shuangyu Luo1
  • Gibae Kim1
  • Hsin-Ru Chan3
  • Wesley J. Wolfe1
7 more authors
  • Lauren G. Zacharias5
  • Thomas P. Mathews5
  • Yi-Chih Lin1
  • Bradley A. Webb4
  • Justin M. Kollman2
  • Xiaolu A. Cambronne3
  • Ku-Lung Hsu1
5 affiliations
  1. 1Department of Chemistry, The University of Texas at Austin, Austin, TX USA
  2. 2Department of Biochemistry, University of Washington, Seattle, WA USA
  3. 3Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX USA
  4. 4Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, WV USA
  5. 5Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX USA
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Abstract

Glycolysis fuels vital cellular functions, and its dysregulation has been implicated in cancer, neurodegeneration, antibiotic resistance and diabetes. The glycolytic dependency of cancer, known as the Warburg effect, represents a key vulnerability for development of targeted anticancer agents; however, the development of such agents remains challenging owing to metabolic heterogeneity and resistance. Here we developed a covalent phosphofructokinase-1 liver type (PFKL) activator that couples glycolytic activation with delivery of a cytotoxic carnitine palmitoyltransferase 2 (CPT2)-targeting payload to cancer cells in vitro and in vivo. The electrophile–drug conjugate site-specifically and proteome-wide selectively modifies K677 in the allosteric effector site to stabilize the R-state tetramer of PFKL, while concomitantly releasing a CPT2-selective inhibitor to destabilize cell metabolism. The delivery mechanism of electrophile–drug conjugates is analogous to that of antibody–drug conjugates, but differentiated by their selective covalent targeting of intracellular proteins.

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Cite

BibTeXRIS
BibTeX
@article{jiang2026covalent,
  title = {{A covalent PFKL activator suppresses tumor growth}},
  author = {Xiaoding Jiang and Eric M. Lynch and Congcong Lyu and Crystal N. Wilson and Lauren E. Salay and Hayden T. Hess and Scott N. Lyons and Mu-Jie Lu and Shuangyu Luo and Gibae Kim and Hsin-Ru Chan and Wesley J. Wolfe and Lauren G. Zacharias and Thomas P. Mathews and Yi-Chih Lin and Bradley A. Webb and Justin M. Kollman and Xiaolu A. Cambronne and Ku-Lung Hsu},
  journal = {Nature Chemical Biology},
  year = {2026},
  month = aug,
  doi = {10.1038/s41589-026-02289-9},
  url = {https://doi.org/10.1038/s41589-026-02289-9},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - A covalent PFKL activator suppresses tumor growth
AU  - Xiaoding Jiang
AU  - Eric M. Lynch
AU  - Congcong Lyu
AU  - Crystal N. Wilson
AU  - Lauren E. Salay
AU  - Hayden T. Hess
AU  - Scott N. Lyons
AU  - Mu-Jie Lu
AU  - Shuangyu Luo
AU  - Gibae Kim
AU  - Hsin-Ru Chan
AU  - Wesley J. Wolfe
AU  - Lauren G. Zacharias
AU  - Thomas P. Mathews
AU  - Yi-Chih Lin
AU  - Bradley A. Webb
AU  - Justin M. Kollman
AU  - Xiaolu A. Cambronne
AU  - Ku-Lung Hsu
PY  - 2026
DA  - 2026/08/05
JO  - Nature Chemical Biology
DO  - 10.1038/s41589-026-02289-9
UR  - https://doi.org/10.1038/s41589-026-02289-9
AB  - Glycolysis fuels vital cellular functions, and its dysregulation has been implicated in cancer, neurodegeneration, antibiotic resistance and diabetes. The glycolytic dependency of cancer, known as the Warburg effect, represents a key vulnerability for development of targeted anticancer agents; however, the development of such agents remains challenging owing to metabolic heterogeneity and resistance. Here we developed a covalent phosphofructokinase-1 liver type (PFKL) activator that couples glycolytic activation with delivery of a cytotoxic carnitine palmitoyltransferase 2 (CPT2)-targeting payload to cancer cells in vitro and in vivo. The electrophile–drug conjugate site-specifically and proteome-wide selectively modifies K677 in the allosteric effector site to stabilize the R-state tetramer of PFKL, while concomitantly releasing a CPT2-selective inhibitor to destabilize cell metabolism. The delivery mechanism of electrophile–drug conjugates is analogous to that of antibody–drug conjugates, but differentiated by their selective covalent targeting of intracellular proteins.
SN  - 1552-4450
SN  - 1552-4469
ER  -