Discovery of N,4-Di(1H-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

doi:10.3390/molecules28072951

Molecules (Mar 2023)

Discovery of N,4-Di(1H-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

DOI: https://doi.org/10.3390/molecules28072951
Journal volume & issue: Vol. 28, no. 7
p. 2951

Abstract

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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.

Published in Molecules

ISSN: 1420-3049 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Chemistry: Organic chemistry
Website: http://www.mdpi.com/journal/molecules

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