Discovery of Novel Substrate-Competitive Lysine Methyltransferase G9a Inhibitors as Anticancer Agents
Discovery of Novel Substrate-Competitive Lysine Methyltransferase G9a Inhibitors as Anticancer Agents
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DOI：
10.1021/acs.jmedchem.2c02059
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发表时间：
2023-03-07
影响因子：
7.3
通讯作者：
Shirai，Fumiyuki
中科院分区：
文献类型：
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作者：
Nishigaya，Yosuke;Takase，Shohei;Shirai，Fumiyuki
结构新颖的赖氨酸甲基转移酶G9 a抑制剂的鉴定一直是癌症表观遗传学研究的主题。从东京大学药物发现计划的化学文库中获得的高通量筛选（HTS）hitrac-10a开始，借助X射线晶体学和配体-蛋白质相互作用的片段分子轨道（FMO）计算，建立了独特的底物竞争性抑制剂的结构-活性关系。进一步优化其体外特性和药物代谢及药代动力学（DMPK）特性，鉴定出26 j（RK-701），其为结构上不同的G9 a/GLP有效抑制剂（IC 50 = 27/53 nM）。化合物26 j对其他相关甲基转移酶表现出显著的选择性，细胞H3 K9 me 2水平的剂量依赖性衰减，以及体外MOLT-4细胞中的肿瘤生长抑制。此外，化合物26 j在致癌物诱导的肝细胞癌（HCC）的小鼠体内模型中显示出肿瘤起始和生长的抑制，而没有明显的急性毒性。
Identification of structurally novel inhibitors of lysine methyltransferase G9a has been a subject of intense research in cancer epigenetics. Starting with the high-throughput screening (HTS) hitrac-10aobtained from the chemical library of the University of Tokyo Drug Discovery Initiative, the structure–activity relationship of the unique substrate-competitive inhibitors was established with the help of X-ray crystallography and fragment molecular orbital (FMO) calculations for the ligand–protein interaction. Further optimization of thein vitrocharacteristics and drug metabolism and pharmacokinetics (DMPK) properties led to the identification of26j(RK-701), which is a structurally distinct potent inhibitor of G9a/GLP (IC50= 27/53 nM). Compound26jexhibited remarkable selectivity against other related methyltransferases, dose-dependent attenuation of cellular H3K9me2 levels, and tumor growth inhibition in MOLT-4 cellsin vitro. Moreover, compound26jshowed inhibition of tumor initiation and growth in a carcinogen-induced hepatocellular carcinoma (HCC)in vivomouse model without overt acute toxicity.