Discovery of N ,4-Di(1 H -pyrazol-4-yl)pyrimidin-2-amine-Derived CDK2 Inhibitors as Potential Anticancer Agents: Design, Synthesis, and Evaluation

• Published in: Molecules (Basel, Switzerland) Switzerland), 2023-03, Vol.28 (7), p.2951
• Main Authors: Fanta, Biruk Sintayehu, Lenjisa, Jimma, Teo, Theodosia, Kou, Lianmeng, Mekonnen, Laychiluh, Yang, Yuchao, Basnet, Sunita K C, Hassankhani, Ramin, Sykes, Matthew J, Yu, Mingfeng, Wang, Shudong
• Format: Article
• Language: English
• Subjects: Amines; Amines - pharmacology; Antineoplastic Agents - pharmacology; antiproliferative activity; Apoptosis; bioisosteric replacement; CDK2; CDK2 inhibitor; Cell division; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase 2; Cyclin-dependent kinases; Design; Humans; Inhibitors; Kinases; Lead compounds; Molecular Structure; N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amine; Neoplasms; Ovarian cancer; Ovarian carcinoma; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Proteins; Pyrazole; Pyrazoles; Pyrazoles - pharmacology; Retinoblastoma; Structure-Activity Relationship; Tumor cell lines
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules28072951

Cyclin-dependent kinase 2 (CDK2) has been garnering considerable interest as a target to develop new cancer treatments and to ameliorate resistance to CDK4/6 inhibitors. However, a selective CDK2 inhibitor has yet to be clinically approved. With the desire to discover novel, potent, and selective CDK2 inhibitors, the phenylsulfonamide moiety of our previous lead compound was bioisosterically replaced with pyrazole derivatives, affording a novel series of ,4-di(1 -pyrazol-4-yl)pyrimidin-2-amines that exhibited potent CDK2 inhibitory activity. Among them, was the most potent CDK2 inhibitor ( = 0.005 µM) with a degree of selectivity over other CDKs tested. Meanwhile, this compound displayed sub-micromolar antiproliferative activity against a panel of 13 cancer cell lines (GI = 0.127-0.560 μM). Mechanistic studies in ovarian cancer cells revealed that reduced the phosphorylation of retinoblastoma at Thr821, arrested cells at the S and G2/M phases, and induced apoptosis. These results accentuate the potential of the ,4-di(1 -pyrazol-4-yl)pyrimidin-2-amine scaffold to be developed into potent and selective CDK2 inhibitors for the treatment of cancer.