A Covalent PFKL Activator Suppresses Tumor Growth

Jiang, X.; Lynch, E. M.; Lyu, C.; Wilson, C.; Salay, L. E.; Lyons, S.; Lu, M.-J.; Luo, S.; Kim, G.; Chan, H.-R.; Wolfe, W.; Lin, Y.-C.; Kollman, J. M.; Cambronne, X. A.; Hsu, K.-L.

doi:10.1101/2025.10.02.680014

bioRxiv · 10.1101/2025.10.02.680014

A Covalent PFKL Activator Suppresses Tumor Growth

Jiang, X.·Lynch, E. M.·Lyu, C.·Wilson, C.·Salay, L. E.·Lyons, S.·Lu, M.-J.·Luo, S.·Kim, G.·Chan, H.-R.·Wolfe, W.·Lin, Y.-C.·Kollman, J. M.·Cambronne, X. A.·Hsu, K.-L.

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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 as a new delivery mechanism analogous to antibody-drug conjugates but differentiated by selective covalent targeting of intracellular proteins.

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Jiang, X., Lynch, E. M., Lyu, C., Wilson, C., Salay, L. E., Lyons, S., Lu, M.-J., Luo, S., Kim, G., Chan, H.-R., Wolfe, W., Lin, Y.-C., Kollman, J. M., Cambronne, X. A., Hsu, K.-L.. 2025-10-03. A Covalent PFKL Activator Suppresses Tumor Growth. https://doi.org/10.1101/2025.10.02.680014

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