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Discovery of liquiritigenin derivatives as PKM2 allosteric inhibitors via targeting the polyarginine pocket.

Xue Wang,Jinpeng Qiu,Jiangbo Xie,Rongbin Huang,Yueliang Chen,Yijun Fang,Yuxuan Tang,Shixiong Wu,Xiangcan Zhou,Zhanchao Chang,Xuenan Wang,Yijun Liu,Sha Jin

Published 2025 in Bioorganic chemistry (Print)

ABSTRACT

Pyruvate kinase M2 (PKM2), a rate-limiting enzyme in glycolysis that modulates immune-related gene expression, represents a potential therapeutic target for LPS endotoxemia. However, the development of allosteric inhibitors targeting PKM2 remains limited. This study employed virtual screening of a natural product library and identified liquiritigenin (LIQ), a flavonoid, as a novel PKM2 allosteric inhibitor, exhibiting an IC50 value of 7.7 ± 2.6 μM. Molecular docking revealed that LIQ binds within a polyarginine pocket with high surface electrostatic potential. Structural modification of LIQ at the 2' position of the B-ring with a critical carboxyl group yielded the derivative LIQ1. This modification substantially reduced its surface electrostatic potential. The protonated carboxyl group of LIQ1 formed ionic interactions and hydrogen bonds with Arg43 of PKM2, resulting in a 20-fold increase in inhibitory potency (IC50 = 0.39 ± 0.04 μM) compared to LIQ. Mutation of PKM2 Arg43 to alanine significantly reduced LIQ1's binding affinity and inhibitory efficacy, identifying Arg43 as a critical residue for the LIQ1-PKM2 interaction. In vivo evaluation revealed that LIQ1 exhibited significantly greater efficacy than LIQ in a model of LPS-induced endotoxemia, resulting in a significant improvement in 7-day survival. LIQ1 treatment prevented the nuclear translocation of PKM2 and inhibited its binding to HIF-1α, thereby suppressing IL-1β transcription, contributing to the therapeutic effect against LPS endotoxemia. Safety evaluations further indicated that LIQ1 exhibited negligible acute toxicity and no evidence of hepatotoxicity or nephrotoxicity. These findings validate LIQ1 as a potent allosteric PKM2 inhibitor targeting Arg43 within the polyarginine pocket, offering a strategy for developing PKM2 allosteric inhibitors.

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