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.
Show 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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