Design, synthesis, and biological evaluation of N-(pyridin-3-yl)pyrimidin-4-amine analogues as novel cyclin-dependent kinase 2 inhibitors for cancer therapy

• Published in: Bioorganic chemistry 2024-02, Vol.143, p.107019-107019, Article 107019
• Main Authors: Zeng, Wen-Bin, Ji, Tang-Yang, Zhang, Yan-Ting, Ma, Yu-Feng, Li, Rou, You, Wen-Wei, Zhao, Pei-Liang
• Format: Article
• Language: English
• Subjects: Antiproliferative activity; CDK2 inhibitor; N-(pyridin-3-yl)pyrimidin-4-amine
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.107019

[Display omitted] •A series of N-(pyridin-3-yl)pyrimidin-4-amine derivatives were synthesized.•IC50 of 7l were 0.83, 2.12, 3.12, and 8.61 on MV4-11, HT29, MCF-7, HeLa.•7l was less toxic on normal embryonic kidney cells HEK293 with high selectivity index.•7l showed potent and similar CDK2 inhibitory activity to AZD5438 with an IC50 of 64.42 nM.•7l caused cell cycle arrest and apoptosis in a concentration-dependent manner. The discovery and development of CDK2 inhibitors has currently been validated as a hot topic in cancer therapy. Herein, a series of novel N-(pyridin-3-yl)pyrimidin-4-amine derivatives were designed and synthesized as potent CDK2 inhibitors. Among them, the most promising compound 7l presented a broad antiproliferative efficacy toward diverse cancer cells MV4-11, HT-29, MCF-7, and HeLa with IC50 values of 0.83, 2.12, 3.12, and 8.61 μM, respectively, which were comparable to that of Palbociclib and AZD5438. Interestingly, these compounds were less toxic on normal embryonic kidney cells HEK293 with high selectivity index. Further mechanistic studies indicated 7l caused cell cycle arrest and apoptosis on HeLa cells in a concentration-dependent manner. Moreover, 7l manifested potent and similar CDK2/cyclin A2 nhibitory activity to AZD5438 with an IC50 of 64.42 nM. These findings revealed that 7l could serve as ahighly promisingscaffoldfor CDK2 inhibitors as potential anticancer agents and functional probes.