Cyclin‐dependent kinases (CDKs) 7 and 9 are deregulated in various types of human cancer and are thus viewed as therapeutic targets. Accordingly, small‐molecule inhibitors of both CDKs are highly sought‐after. Capitalising on our previous discovery of CDKI‐73, a potent CDK9 inhibitor, medicinal chemistry optimisation was pursued. A number of N‐pyridinylpyrimidin‐2‐amines were rationally designed, chemically synthesised and biologically assessed. Among them, N‐(6‐(4‐cyclopentylpiperazin‐1‐yl)pyridin‐3‐yl)‐4‐(imidazo[1,2‐a]pyrimidin‐3‐yl)pyrimidin‐2‐amine was found to be one of the most potent inhibitors of CDKs 7 and 9 as well as the most effective anti‐proliferative agent towards multiple human cancer cell lines. The cellular mode of action of this compound was investigated in MV4‐11 acute myeloid leukaemia cells, revealing that the compound dampened the kinase activity of cellular CDKs 7 and 9, arrested the cell cycle at sub‐G1 phase and induced apoptosis.
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 1 was bioisosterically replaced with pyrazole derivatives, affording a novel series of N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amines that exhibited potent CDK2 inhibitory activity. Among them, 15 was the most potent CDK2 inhibitor (Ki = 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 (GI50 = 0.127–0.560 μM). Mechanistic studies in ovarian cancer cells revealed that 15 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 N,4-di(1H-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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