Ginsenoside F2 inhibits MLCK to induce synthetic lethality in MYC-driven triple-negative breast cancer and pancreatic cancer

IF 1.3 4区生物学 Q4 CHEMISTRY, MEDICINAL

Phytochemistry Letters Pub Date : 2025-03-26 DOI:10.1016/j.phytol.2025.102949

Rui Wu , Dong Lu , Xin Luan , Weidong Zhang , Zhe Sun

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引用次数: 0

Abstract

Myosin Light Chain Kinase (MLCK) represents a synthetic lethal interaction with the “undruggable” oncoprotein MYC. In this study, we identified Ginsenoside F2 (GF2) as a novel MLCK inhibitor through molecular docking-based virtual screening of a natural compound library, followed by in vitro cellular validation. GF2 treatment inhibited MLCK kinase activity, as demonstrated by the reduced phosphorylation of its substrate, myosin II regulatory light chain (MLC). The direct binding of GF2 to MLCK was confirmed using the cellular thermal shift assay (CETSA), which revealed decreased MLCK thermotolerance after GF2 treatment. Notably, GF2 selectively induced apoptosis in MYC-transformed cells while sparing normal counterparts. Triple-negative breast cancer (TNBC) and pancreatic cancer cells with high MYC expression are sensitive to GF2 treatment. Moreover, combining GF2 with the Bcl2 inhibitor venetoclax synergistically enhanced apoptosis in MYC-driven cancer cells. These findings establish GF2 as a novel MLCK inhibitor and underscore the therapeutic potential of targeting MLCK in MYC-driven malignancies, particularly TNBC and pancreatic cancer.

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来源期刊

Phytochemistry Letters 生物-生化与分子生物学

CiteScore

3.00

自引率

11.80%

发文量

190

审稿时长

34 days

期刊介绍： Phytochemistry Letters invites rapid communications on all aspects of natural product research including: • Structural elucidation of natural products • Analytical evaluation of herbal medicines • Clinical efficacy, safety and pharmacovigilance of herbal medicines • Natural product biosynthesis • Natural product synthesis and chemical modification • Natural product metabolism • Chemical ecology • Biotechnology • Bioassay-guided isolation • Pharmacognosy • Pharmacology of natural products • Metabolomics • Ethnobotany and traditional usage • Genetics of natural products Manuscripts that detail the isolation of just one new compound are not substantial enough to be sent out of review and are out of scope. Furthermore, where pharmacology has been performed on one new compound to increase the amount of novel data, the pharmacology must be substantial and/or related to the medicinal use of the producing organism.