2-Anilino-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine-derived CDK2 inhibitors as anticancer agents: Design, synthesis & evaluation. (15th February 2023)

• Record Type: Journal Article
• Authors: Fanta, Biruk Sintayehu; Mekonnen, Laychiluh; Basnet, Sunita K.C.; Teo, Theodosia; Lenjisa, Jimma; Khair, Nishat Z.; Kou, Lianmeng; Tadesse, Solomon; Sykes, Matthew J.; Yu, Mingfeng; Wang, Shudong
• Is Part Of: Bioorganic & medicinal chemistry. Volume 80(2023)
• Publication Date: 2023-02-15
• Subjects: CDK2 -- CDK2 inhibitor -- 2-Anilino-4-(1-methyl-1H-pyrazol-4-yl)pyrimidine -- Antiproliferative activity -- Bioisosteric replacement -- CDKI-73; CDK: Cyclin-dependent kinase -- CDK2: Cyclin-dependent kinase 2 -- CDK1B: CDK1-cyclin B -- CDK2E: CDK2-cyclin E -- CDK5p25: CDK5-p25 -- CDK9T1: CDK9-cyclin T1 -- GI: Growth inhibition -- ALK: Anaplastic lymphoma kinase -- ATP: Adenosine triphosphate -- CAK: CDK-activating kinase -- CDC25: Cell division cycle 25 -- CIP: CDK-interacting protein -- KIP: Kinase inhibitory protein -- DNA: Deoxyribonucleic acid -- E2F: E2 promoter binding factor -- FGFR: Fibroblast growth factor receptor -- HER2-: Human epidermal growth factor receptor 2-negative -- HR+: Hormone receptor-positive -- MCL1: Myeloid cell leukaemia 1 -- MTT: 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide -- PARP: Poly(ADP-ribose) polymerase -- RET: Rearranged during transfection -- Rb: Retinoblastoma; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2023.117158
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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-1 H -pyrazol-4-yl)pyrimidine series in developing potent and selective CDK2 inhibitors to combat cancer.