Discovery of an Orally Efficacious MYC Inhibitor for Liver Cancer Using a GNMT-Based High-Throughput Screening System and Structure–Activity Relationship Analysis

• Published in: Journal of medicinal chemistry Vol. 64; no. 13; pp. 8992 - 9009
• Main Authors: Kant, Rajni, Yang, Ming-Hui, Tseng, Chih-Hua, Yen, Chia-Hung, Li, Wei-You, Tyan, Yu-Chang, Chen, Marcelo, Tzeng, Cherng-Chyi, Chen, Wei-Cheng, You, Kaiting, Wang, Wen-Chieh, Chen, Yeh-Long, Chen, Yi-Ming Arthur
• Format: Journal Article
• Language: English
• Published: American Chemical Society 08.07.2021
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00093

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.