Discovery of <i>N</i>,4-Di(1<i>H</i>-pyrazol-4-yl)pyrimidin-2-amine-Derived CDK2 Inhibitors as Potential Anticancer Agents: Design, Synthesis, and Evaluation
Biruk Sintayehu Fanta,
Jimma Lenjisa,
Theodosia Teo,
Lianmeng Kou,
Laychiluh Mekonnen,
Yuchao Yang,
Sunita K. C. Basnet,
Ramin Hassankhani,
Matthew J. Sykes,
Mingfeng Yu,
Shudong Wang
Affiliations
Biruk Sintayehu Fanta
Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
Jimma Lenjisa
Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
Theodosia Teo
Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
Lianmeng Kou
Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
Laychiluh Mekonnen
Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
Yuchao Yang
Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
Sunita K. C. Basnet
Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
Ramin Hassankhani
Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
Matthew J. Sykes
Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
Mingfeng Yu
Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
Shudong Wang
Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
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.
