國家衛生研究院 NHRI:Item 3990099045/13488
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    题名: Discovery of an orally efficacious MYC inhibitor for liver cancer using a GNMT-based high-throughput screening system and structure-activity relationship analysis
    作者: Kant, R;Yang, MH;Tseng, CH;Yen, CH;Li, WY;Tyan, YC;Chen, M;Tzeng, CC;Chen, WC;You, K;Wang, WC;Chen, YL;Chen, YAM
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: Glycine-N-methyl transferase (GNMT) downregulation results in spontaneous hepatocellular carcinoma (HCC). Overexpression of GNMT inhibits the proliferation of liver cancer cell lines and prevents carcinogen-induced HCC, suggesting that GNMT induction is a potential approach for anti-HCC therapy. Herein, we used Huh7 GNMT promoter-driven screening to identify a GNMT inducer. Compound K78 was identified and validated for its induction of GNMT and inhibition of Huh7 cell growth. Subsequently, we employed structure-activity relationship analysis and found a potent GNMT inducer, K117. K117 inhibited Huh7 cell growth in vitro and xenograft in vivo. Oral administration of a dosage of K117 at 10 mpk (milligrams per kilogram) can inhibit Huh7 xenograft in a manner equivalent to the effect of sorafenib at a dosage of 25 mpk. A mechanistic study revealed that K117 is an MYC inhibitor. Ectopic expression of MYC using CMV promoter blocked K117-mediated MYC inhibition and GNMT induction. Overall, K117 is a potential lead compound for HCC- and MYC-dependent cancers.
    日期: 2021-06-16
    關聯: Journal of Medicinal Chemistry. 2021 Jun 16;64(13):8992-9009.
    Link to: http://dx.doi.org/10.1021/acs.jmedchem.1c00093
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0022-2623&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000672729800009
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85110190123
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