Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China.
State Key Laboratory of Drug Research, The Center for Chemical Biology, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):1537-1555. doi: 10.1080/14756366.2022.2079640.
The DNA methyltransferases (DNMTs) were found in mammals to maintain DNA methylation. Among them, DNMT1 was the first identified, and it is an attractive target for tumour chemotherapy. DC_05 and DC_517 have been reported in our previous work, which is non-nucleoside DNMT1 inhibitor with low micromolar IC values and significant selectivity towards other S-adenosyl--methionine (SAM)-dependent protein methyltransferases. In this study, through a process of similarity-based analog searching, a series of DNMT1 inhibitors were designed, synthesized, and evaluated as anticancer agents. SAR studies were conducted based on enzymatic assays. And most of the compounds showed strong inhibitory activity on human DNMT1, especially WK-23 displayed a good inhibitory effect on human DNMT1 with an IC value of 5.0 µM. Importantly, the pharmacokinetic (PK) profile of WK-23 was obtained with quite satisfying oral bioavailability and elimination half-life. Taken together, WK-23 is worth developing as DNMT1-selective therapy for the treatment of malignant tumour.
DNA 甲基转移酶 (DNMTs) 在哺乳动物中被发现可以维持 DNA 甲基化。其中，DNMT1 是最早被鉴定的，它是肿瘤化疗的一个有吸引力的靶点。在我们之前的工作中已经报道了 DC_05 和 DC_517，它是一种非核苷类 DNMT1 抑制剂，对其他 S-腺苷甲硫氨酸 (SAM)-依赖性蛋白甲基转移酶具有低微摩尔 IC 值和显著的选择性。在这项研究中，通过基于相似性的类似物搜索过程，设计、合成并评估了一系列 DNMT1 抑制剂作为抗癌剂。基于酶促测定进行了 SAR 研究。并且大多数化合物对人 DNMT1 表现出很强的抑制活性，特别是 WK-23 对人 DNMT1 的抑制作用较好，IC 值为 5.0μM。重要的是，获得了 WK-23 的药代动力学 (PK) 特征，具有相当令人满意的口服生物利用度和消除半衰期。综上所述，WK-23 值得作为治疗恶性肿瘤的 DNMT1 选择性治疗药物进行开发。
