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<p>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.</p><p></p>

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A covalent PFKL activator suppresses tumor growth

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月5日

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  • Xiaoding Jiang,
  • Eric M. Lynch,
  • Congcong Lyu,
  • Crystal N. Wilson,
  • Lauren E. Salay,
  • Hayden T. Hess,
  • Scott N. Lyons,
  • Mu-Jie Lu,
  • Shuangyu Luo,
  • Gibae Kim,
  • Hsin-Ru Chan,
  • Wesley J. Wolfe,
  • Lauren G. Zacharias,
  • Thomas P. Mathews,
  • Yi-Chih Lin,
  • Bradley A. Webb,
  • Justin M. Kollman,
  • Xiaolu A. Cambronne,
  • Ku-Lung Hsu

摘要

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.