亚甲基四氢叶酸脱氢酶2(MTHFD2)小分子抑制剂研究进展

Recent Advances in the Small-Molecule Inhibitors of Targeting Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2)

为了维持增殖,肿瘤细胞依赖于一碳代谢来支持嘌呤和嘧啶核苷酸的合成。亚甲基四氢叶酸脱氢酶2(Methyle-netetrahydrofolate Dehydrogenase 2,MTHFD2)是肿瘤转化过程中上调程度最高的酶之一,作为线粒体亚甲基四氢叶酸脱氢酶和环水解酶参与一碳代谢。由于MTHFD2仅在胚胎发育期间正常表达,而在正常成人组织不表达或低表达,因此这为根除肿瘤细胞同时保留正常细胞提供了选择性的治疗靶点。综述了近年来已报道的MTHFD2抑制剂的开发、优化和最新进展,讨论其作为抗肿瘤药物的治疗潜力,并提出未来开发的潜在挑战。

To sustain proliferation,tumor cells rely on one-carbon metabolism to support the synthesis of purine and pyrimidine nucleotides.Methylenetetrahydrofolate dehydrogenase 2(MTHFD2)is one of the most highly upregulated enzymes in tumor transformation,and functions as a mitochondrial methylenetetrahydrofolate dehydrogenase and cyclohydrolase involved in one-carbon metabolism.Due to its exclusive expression during embryonic development but minimal or absent expression in normal adult tissues,MTHFD2 provides a selectively targetable therapeutic option for eradicating tumor cells while preserving normal cells.This review summarized the development,optimization,and latest progress of MTHFD2 inhibitors reported to date,discussed their therapeutic potential as anticancer agents and highlights potential challenges for future development.