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

被引：10

作者：

Kant, Rajni ^{[1
]}

Yang, Ming-Hui ^{[2
]}

Tseng, Chih-Hua ^{[3
,4
]}

Yen, Chia-Hung ^{[5
,6
]}

Li, Wei-You ^{[1
]}

Tyan, Yu-Chang ^{[7
]}

Chen, Marcelo ^{[8
]}

Tzeng, Cherng-Chyi ^{[9
]}

Chen, Wei-Cheng ^{[1
]}

You, Kaiting ^{[1
]}

Wang, Wen-Chieh ^{[10
]}

Chen, Yeh-Long ^{[4
,9
]}

Chen, Yi-Ming Arthur ^{[1
]}

机构：

[1] Fu Jen Catholic Univ, Grad Inst Biomed & Pharmaceut Sci, New Taipei 24205, Taiwan

[2] Kaohsiung Vet Gen Hosp, Dept Med Educ & Res, Kaohsiung 81362, Taiwan

[3] Kaohsiung Med Univ, Coll Pharm, Sch Pharm, Kaohsiung 807, Taiwan

[4] Kaohsiung Med Univ, Drug Dev & Value Creat Res Ctr, Kaohsiung 80708, Taiwan

[5] Kaohsiung Med Univ, Grad Inst Nat Prod, Coll Pharm, Kaohsiung 80708, Taiwan

[6] Kaohsiung Med Univ, Res Ctr Nat Prod & Drug Dev, Kaohsiung 80708, Taiwan

[7] Kaohsiung Med Univ, Dept Med Imaging & Radiol Sci, Kaohsiung 80708, Taiwan

[8] Mackay Mem Hosp, Dept Urol, Taipei 10449, Taiwan

[9] Kaohsiung Med Univ, Coll Life Sci, Dept Med & Appl Chem, Kaohsiung 80708, Taiwan

[10] Natl Hlth Res Inst, Inst Biotechnol & Pharmaceut Res, Zhunan 35053, Miaoli County, Taiwan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 13期

关键词：

GLYCINE-N-METHYLTRANSFERASE; ADVANCED HEPATOCELLULAR-CARCINOMA; TRANSITION-METAL-COMPLEXES; C-MYC; COST-EFFECTIVENESS; G-QUADRUPLEX; SORAFENIB; CELLS; BINDING; AROYLHYDRAZONE;

D O I：

10.1021/acs.jmedchem.1c00093

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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.

引用

页码：8992 / 9009

页数：18