Key Laboratory of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education. College of Life Science and Technology, Beijing University of Chemical Technology, 15 Beisanhuan East Road, Beijing, 100029, China.
Key Laboratory of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education. College of Life Science and Technology, Beijing University of Chemical Technology, 15 Beisanhuan East Road, Beijing, 100029, China.
Eur J Med Chem. 2020 Jul 15;198:112322. doi: 10.1016/j.ejmech.2020.112322. Epub 2020 Apr 23.
In the current study, we have designed and synthesized a series of novel histone deacetylase1/2 (HDAC1/2) and cyclin-dependent kinase2 (CDK2) dual inhibitors by integrating purine-based pharmacophore into the recognition cap group of CS055. The representative compound 14d with excellent antiproliferative activities towards five solid cancer cells, showed potent inhibitory activities against HDAC1, HDAC2 and CDK2 with IC values of 70.7 nM, 23.1 nM and 0.80 μM, respectively. Besides, compound 14d could effectively block the cell cycle in the G2/M phase and induce apoptosis, which might be related to increasing intracellular ROS levels. Importantly, compound 14d exhibited desirable pharmacokinetic (PK) properties with the intraperitoneal bioavailability of 50.8% in ICR mice, and potent in vivo antitumor activity in the HCT116 xenograft model. Therefore, compound 14d could be considered as a promising lead compound for the development of multitargeting anticancer agents.
在本研究中，我们通过将嘌呤基药效团整合到 CS055 的识别帽基团中，设计并合成了一系列新型组蛋白去乙酰化酶 1/2（HDAC1/2）和细胞周期蛋白依赖性激酶 2（CDK2）双重抑制剂。具有优异的抗增殖活性的代表性化合物 14d 对五种实体癌细胞表现出很强的抑制活性，对 HDAC1、HDAC2 和 CDK2 的抑制活性分别为 70.7 nM、23.1 nM 和 0.80 μM。此外，化合物 14d 可以有效地将细胞周期阻滞在 G2/M 期并诱导细胞凋亡，这可能与增加细胞内 ROS 水平有关。重要的是，化合物 14d 在 ICR 小鼠中具有良好的药代动力学（PK）性质，腹腔内生物利用度为 50.8%，在 HCT116 异种移植模型中具有很强的体内抗肿瘤活性。因此，化合物 14d 可以被认为是一种有前途的用于开发多靶点抗癌药物的先导化合物。
