4.7 Article

Imidazo[1,2-c]pyrimidin-5(6H)-one inhibitors of CDK2: Synthesis, kinase inhibition and co-crystal structure

期刊

出版社

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113309

关键词

Kinase inhibitor; Cyclin-dependent kinase 2; imidazo[1,2-c]pyrimidin-5(6H)-one; X-ray crystallography; Co-crystal; Activity assay; ITC

资金

  1. Czech Science Foundation [GA 19-08410S]
  2. European Regional Development Fund (Project ENOCH) [CZ.02.1.01/0.0/0.0/16_019/0000868]
  3. European Regional Development Fund (Project ChemBioDrug) [CZ.02.1.01/0.0/0.0/16_019/0000729]

向作者/读者索取更多资源

This study presents a series of substituted imidazo[1,2-c]pyrimidines as inhibitors of cyclin-dependent kinase 2 (CDK2), synthesized using various methods including Suzuki-Miyaura cross-coupling and halogenation. The compounds exhibited micro-to submicromolar inhibition of CDK2/cyclin E activity, with one compound showing strong binding to CDK2 and high selectivity against leukemia cell lines. This research suggests the potential of substituted imidazo[1,2-c]pyrimidines for future kinase inhibitor development.
Pharmacological inhibition of cyclin-dependent kinases has emerged as a possible treatment option for various cancer types. We recently identified substituted imidazo[1,2-c]pyrimidin-5(6H)-ones as inhibitors of cyclin-dependent kinase 2 (CDK2). Here, we report the synthesis of derivatives modified at positions 2, 3, 6 or 8 prepared using Suzuki-Miyaura cross-coupling, halogenation, Dimroth-type rearrangement and alkylation as the main synthetic methods. The compounds displayed micro-to submicromolar inhibition of CDK2/cyclin E activity. Binding of the most potent compound 3b to CDK2 was determined using isothermal titration calorimetry. The co-crystal structure of 3b in complex with fully active CDK2 was solved, revealing the binding mode of 3b in the ATP pocket and a hydrogen bonding interaction with hinge region residue Leu83. Evaluation against leukaemia cell lines revealed low cytotoxicity, which is in line with the high selectivity towards CDK2. This study demonstrates that substituted imidazo[1,2-c]pyrimidines can be exploited for future kinase inhibitor development. (C) 2021 Elsevier Masson SAS. All rights reserved.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据