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

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.