| Summary: | 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 <b>1</b> was bioisosterically replaced with pyrazole derivatives, affording a novel series of <i>N</i>,4-di(1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amines that exhibited potent CDK2 inhibitory activity. Among them, <b>15</b> was the most potent CDK2 inhibitor (<i>K</i><sub>i</sub> = 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<sub>50</sub> = 0.127–0.560 μM). Mechanistic studies in ovarian cancer cells revealed that <b>15</b> 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 <i>N</i>,4-di(1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amine scaffold to be developed into potent and selective CDK2 inhibitors for the treatment of cancer.
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