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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 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 (EDC) 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. We introduce EDCs as a new delivery mechanism analogous to antibody-drug conjugates but differentiated by selective covalent targeting of intracellular proteins.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Monocyte, Leukocyte, Melanocyte, Epithelial Cell, Cell Culture, Macrophage

DISEASE(S): Melanoma

SUBMITTER: Ku-Lung Hsu

LAB HEAD: Ku-Lung Hsu

PROVIDER: PXD078921 | Pride | 2026-06-18

REPOSITORIES: Pride

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			Action	DRS
	20251112_VaPa_XJ14_XJ_XJ-8-45_B16_TPP_CCR_B1-F1_T1.raw	Raw
	20251112_VaPa_XJ14_XJ_XJ-8-45_B16_TPP_CCR_B1-F2_T1.raw	Raw
	20251112_VaPa_XJ14_XJ_XJ-8-45_B16_TPP_CCR_B1-F3_T1.raw	Raw
	20251112_VaPa_XJ14_XJ_XJ-8-45_B16_TPP_CCR_B1-F4_T1.raw	Raw
	20251112_VaPa_XJ14_XJ_XJ-8-45_B16_TPP_CCR_B1-F5_T1.raw	Raw

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