國家衛生研究院 NHRI:Item 3990099045/16433
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    題名: Development of potent and selective inhibitors of methylenetetrahydrofolate dehydrogenase 2 for targeting acute myeloid leukemia: Sar, structural insights, and biological characterization
    作者: Chang, HH;Lee, LC;Hsu, T;Peng, YH;Huang, CH;Yeh, TK;Lu, CT;Huang, ZT;Hsueh, CC;Kung, FC;Lin, LM;Huang, YC;Wang, YH;Li, LH;Tang, YC;Chang, L;Hsieh, CC;Jiaang, WT;Kuo, CC;Wu, SY
    貢獻者: Institute of Biotechnology and Pharmaceutical Research
    摘要: Methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2), a pivotal mitochondrial enzyme in one-carbon metabolism, is significantly upregulated in various cancers but minimally expressed in normal proliferating cells. In contrast, MTHFD1, which performs similar functions, is predominantly expressed in normal cells. Therefore, targeting MTHFD2 with selective inhibitors holds promise for a broader therapeutic window with reduced toxicity and fewer side effects. This study identified selective 2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl ureido-based derivatives through systematic chemical modifications and SAR studies. Structural biology investigations revealed substitutions in the phenyl ring and tail region modulate potency and selectivity toward MTHFD2. Additionally, a comprehensive cell screening platform revealed acute myeloid leukemia cells with FLT3 internal tandem duplication mutations are particularly sensitive to these inhibitors. Furthermore, synergistic effects were observed when combining potential compounds with Alimta. Compound 16e emerged as a leading candidate, demonstrating superior inhibition and selectivity for MTHFD2, favorable pharmacokinetics, and potent antitumor efficacy in MOLM-14 xenograft models.
    日期: 2024-11-26
    關聯: Journal of Medicinal Chemistry. 2024 Nov 26;67(23):21106-21125.
    Link to: http://dx.doi.org/10.1021/acs.jmedchem.4c01775
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:001363868900001
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85210297623
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