Li Chunzheng, Lan Xiaojing, Li Xinge, Fu Yixian, Gui Gang, Li Xiaodong, Shen Yanyan, Gan Zhenjie, Huang Min, Zha Xiaoming
Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
J Med Chem. 2025 Jan 23;68(2):1222-1244. doi: 10.1021/acs.jmedchem.4c01635. Epub 2025 Jan 6.
Methionine adenosyltransferase 2A (MAT2A) has emerged as a synthetic lethal drug target in cancers bearing homozygous methylthioadenosine phosphorylase (MTAP) gene deletion. Despite the remarkable progress in the discovery and development of MAT2A inhibitors, current understanding about the selectivity of these compounds toward MTAP-deficient cancers is relatively limited. To improve the selectivity of MAT2A inhibitors for MTAP-deficient cancers remains a significant challenge. We herein reported the discovery of a series of novel MAT2A inhibitors with a 2(1)-quinoxalinone scaffold through structure-based drug design and systematic SAR exploration. Among them, compound exhibited good inhibitory activity against the enzymatic activity of MAT2A, and the significantly improved selectivity in killing MTAP-deficient cancer cells. Compound also showed favorable pharmacokinetic properties and the improved in vivo anticancer activity in MTAP-deficient tumor models. These findings suggest new directions for the discovery and development of highly selective MAT2A inhibitors.
甲硫氨酸腺苷转移酶2A（MAT2A）已成为携带纯合甲基硫代腺苷磷酸化酶（MTAP）基因缺失的癌症中的合成致死药物靶点。尽管在MAT2A抑制剂的发现和开发方面取得了显著进展，但目前对这些化合物对MTAP缺陷型癌症的选择性的了解相对有限。提高MAT2A抑制剂对MTAP缺陷型癌症的选择性仍然是一项重大挑战。我们在此报告通过基于结构的药物设计和系统的构效关系探索发现了一系列具有2(1)-喹喔啉酮骨架的新型MAT2A抑制剂。其中，化合物对MAT2A的酶活性表现出良好的抑制活性，并且在杀死MTAP缺陷型癌细胞方面具有显著提高的选择性。化合物还表现出良好的药代动力学性质，并在MTAP缺陷型肿瘤模型中提高了体内抗癌活性。这些发现为高选择性MAT2A抑制剂的发现和开发提供了新的方向。
