2-Anilino-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine-derived CDK2 inhibitors as anticancer agents: Design, synthesis & evaluation

Biruk Sintayehu Fanta; Laychiluh Mekonnen; Sunita K C Basnet; Theodosia Teo; Jimma Lenjisa; Nishat Z Khair; Lianmeng Kou; Solomon Tadesse; Matthew J Sykes; Mingfeng Yu; Shudong Wang

doi:10.1016/j.bmc.2023.117158

2-Anilino-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine-derived CDK2 inhibitors as anticancer agents: Design, synthesis & evaluation

Bioorg Med Chem. 2023 Feb 15:80:117158. doi: 10.1016/j.bmc.2023.117158. Epub 2023 Jan 11.

Affiliations

¹ Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia 5000, Australia.
² Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia 5000, Australia. Electronic address: Mingfeng.Yu@unisa.edu.au.
³ Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia 5000, Australia. Electronic address: Shudong.Wang@unisa.edu.au.

PMID: 36706608
DOI: 10.1016/j.bmc.2023.117158

Abstract

Deregulation of cyclin-dependent kinase 2 (CDK2) and its activating partners, cyclins A and E, is associated with the pathogenesis of a myriad of human cancers and with resistance to anticancer drugs including CDK4/6 inhibitors. Thus, CDK2 has become an attractive target for the development of new anticancer therapies and for the amelioration of the resistance to CDK4/6 inhibitors. Bioisosteric replacement of the thiazole moiety of CDKI-73, a clinically trialled CDK inhibitor, by a pyrazole group afforded 9 and 19 that displayed potent CDK2-cyclin E inhibition (K_i = 0.023 and 0.001 μM, respectively) with submicromolar antiproliferative activity against a panel of cancer cell lines (GI₅₀ = 0.025-0.780 μM). Mechanistic studies on 19 with HCT-116 colorectal cancer cells revealed that the compound reduced the phosphorylation of retinoblastoma at Ser807/811, arrested the cells at the G2/M phase, and induced apoptosis. These results highlight the potential of the 2-anilino-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine series in developing potent and selective CDK2 inhibitors to combat cancer.

Keywords: 2-Anilino-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine; Antiproliferative activity; Bioisosteric replacement; CDK2; CDK2 inhibitor; CDKI-73.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / pharmacology
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinases / metabolism
Humans
Neoplasms*
Pyrazoles / pharmacology
Pyrimidines / pharmacology

Substances

Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinases
Antineoplastic Agents
Pyrimidines
Pyrazoles
CDK2 protein, human