Discovery of 2-tetrahydroisoquinoline substituted quinazoline derivatives as lysine methyltransferase G9a inhibitors with in vivo antitumor efficacy
文献类型：期刊论文
| 作者 | Shao, Mengjie5; Gao, Lixin3; Xu, Jiahui5; Zhu, Lingfeng4; Lu, Yiting4; Jiang, Kailong2; Sun, Jia5; Jiang, Xiaolong3; Li, Jia2,3; Zhang, Ao4 |
| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2025-12-15 |
| 卷号 | 300页码:15 |
| 关键词 | Lysine methyltransferase G9a inhibitor Structural optimization Tetrahydroisoquinoline Antitumor |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2025.118113 |
| 通讯作者 | Zhang, Ao(ao6919zhang@sjtu.edu.cn) ; Zhou, Yubo(ybzhou@simm.ac.cn) ; Ding, Chunyong(chunding@sjtu.edu.cn) |
| 英文摘要 | Overexpression of protein lysine methyltransferase G9a, which catalyzes mono- and di-methylation of histone H3K9 and non-histone proteins, is closely associated with poor prognosis and metastasis of various cancers. Here, we designed and synthesized a series of novel G9a inhibitors bearing 2-tetrahydroisoquinoline substituted quinazoline scaffold. Among them, compound 31 with 2-dioxole fused tetrahydroisoquinoline exhibited the most potent inhibitory effects against G9a with an IC50 value of 0.032 mu M and high selectivity against the other tested lysine/arginine methyltransferases. Molecular docking showed that the bulky tricyclic moiety of compound 31 enhanced its interaction with the active sites of G9a through additional van der Waals forces. Compared to the reference compound UNC0642, compound 31 exhibited much improved enzymatic activity against G9a and more potent antiproliferative effects against all tested cancer cells. In CT26 colon cells, this compound not only significantly suppressed the H3K9me2 level, but also triggered autophagy by inducing the production of ROS, thus leading to cell apoptosis and cell cycle arrest at G0/G1. It also possessed good microsomal metabolic stability and acceptable in vivo pharmacokinetic properties. More importantly, in the CT26 tumor mouse model, compound 31 demonstrated in vivo antitumor efficacy with a TGI rate of 45.10 % without significant body weight loss and visible toxicity, indicating a superior safety profile compared to UNC0642. Overall, compound 31 with 2-tetrahydroisoquinoline substituted quinazoline scaffold could be used as a promising lead compound for the development of novel G9a inhibitors. |
| WOS关键词 | HISTONE METHYLTRANSFERASE ; CHEMICAL PROBE ; METHYLATION ; COMPLEXES ; COGNITION ; SURVIVAL ; GENES |
| 资助项目 | National Natural Science Foundation of China[22177068] ; National Key R & D Program of China[2022YFF1203005] ; Shanghai Committee of Science and Technology[24ZR1491100] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001568020500002 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321471]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Zhang, Ao; Zhou, Yubo; Ding, Chunyong |
| 作者单位 | 1.Shanghai Pharmaceut Holding Co Ltd, Cent Res Inst, State Key Lab Innovat Immunotherapy, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China 3.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 4.Wenzhou Med Univ, Chem Biol Res Ctr, Sch Pharmaceut Sci, Wenzhou 325035, Peoples R China 5.Shanghai Jiao Tong Univ, Shanghai Frontiers Sci Ctr Drug Target Identificat, Natl Key Lab Innovat Immunotherapy, Sch Pharmaceut Sci, Shanghai 200240, Peoples R China |
| 推荐引用方式 GB/T 7714 | Shao, Mengjie,Gao, Lixin,Xu, Jiahui,et al. Discovery of 2-tetrahydroisoquinoline substituted quinazoline derivatives as lysine methyltransferase G9a inhibitors with in vivo antitumor efficacy[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2025,300:15. |
| APA | Shao, Mengjie.,Gao, Lixin.,Xu, Jiahui.,Zhu, Lingfeng.,Lu, Yiting.,...&Ding, Chunyong.(2025).Discovery of 2-tetrahydroisoquinoline substituted quinazoline derivatives as lysine methyltransferase G9a inhibitors with in vivo antitumor efficacy.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,300,15. |
| MLA | Shao, Mengjie,et al."Discovery of 2-tetrahydroisoquinoline substituted quinazoline derivatives as lysine methyltransferase G9a inhibitors with in vivo antitumor efficacy".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 300(2025):15. |
入库方式： OAI收割
来源：上海药物研究所
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