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Discovery of an Orally Efficacious MYC Inhibitor for Liver Cancer Using a GNMT-Based High-Throughput Screening System
Rajni Kant1, Ming-Hui Yang2, Chih-Hua Tseng3,4
1Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City 24205, Taiwan.
Abstract:
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.
Insights
Glycine-N-methyl transferase (GNMT) downregulation causes liver cancer. Researchers identified K117, a compound that induces GNMT and inhibits hepatocellular carcinoma (HCC) growth by targeting MYC.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Glycine-N-methyl transferase (GNMT) downregulation is linked to hepatocellular carcinoma (HCC) development.
- GNMT overexpression demonstrates anti-cancer properties, suggesting GNMT induction as a therapeutic strategy for HCC.
Purpose of the Study:
- To identify novel inducers of GNMT for potential anti-HCC therapy.
- To evaluate the efficacy and mechanism of action of identified GNMT inducers.
Main Methods:
- Utilized Huh7 GNMT promoter-driven screening to identify GNMT inducers.
- Conducted structure-activity relationship analysis to optimize compound potency.
- Performed in vitro and in vivo studies using cell lines and xenografts.
- Investigated the molecular mechanism, including MYC inhibition.
Main Results:
- Identified compound K78 as an initial GNMT inducer and inhibitor of Huh7 cell growth.
- Discovered compound K117, a potent GNMT inducer with significant in vitro and in vivo anti-cancer activity.
- K117 demonstrated efficacy comparable to sorafenib in inhibiting Huh7 xenografts.
- Mechanistic studies revealed K117 as an MYC inhibitor, with MYC expression blocking K117's effects.
Conclusions:
- K117 is a promising lead compound for treating HCC.
- K117's efficacy is dependent on MYC inhibition, suggesting its potential for MYC-dependent cancers.
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