A Covalent PFKL Activator Suppresses Tumor Growth.

ABSTRACT: Glycolysis fuels vital cellular functions and its dysregulation is implicated in cancer, neurodegeneration, antibiotic resistance and diabetes. The glycolytic dependency of cancer, known as the Warburg effect, presents a key vulnerability for developing targeted anticancer agents but remains challenging due to metabolic heterogeneity and resistance. Here, we developed a first-in-class covalent phosphofructokinase-1 liver type (PFKL) activator that induces metabolic imbalance coupled to delivery of a cytotoxic payload to cancer cells in vitro and in vivo. The electrophile-drug conjugate (EDC) site-specifically and proteome-wide selectively modifies K677 in the allosteric effector site to stabilize the R-state tetramer of PFKL and destabilize cell metabolism. We introduce EDCs

SUBMITTER: Jiang X 

PROVIDER: S-EPMC12621983 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature