7ACK

CDK2/cyclin A2 in complex with an imidazo[1,2-c]pyrimidin-5-one inhibitor

7ACK の概要

• エントリーDOI: 10.2210/pdb7ack/pdb
• 分子名称: Cyclin-dependent kinase 2, Cyclin-A2, 8-cyclohexyl-6~{H}-imidazo[1,2-c]pyrimidin-5-one, ... (7 entities in total)
• 機能のキーワード: cyclin-dependent kinase 2, substituted imidazo[1, 2-c]pyrimidin-5-one, inhibitor, cell cycle
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 128823.02

構造登録者

Skerlova, J.,Pachl, P.,Rezacova, P. (登録日: 2020-09-11, 公開日: 2021-03-24, 最終更新日: 2024-11-20)

主引用文献

Jansa, J.,Jorda, R.,Skerlova, J.,Pachl, P.,Perina, M.,Reznickova, E.,Heger, T.,Gucky, T.,Rezacova, P.,Lycka, A.,Krystof, V.
Imidazo[1,2-c]pyrimidin-5(6H)-one inhibitors of CDK2: Synthesis, kinase inhibition and co-crystal structure.
Eur.J.Med.Chem., 216:113309-113309, 2021

PubMed Abstract: 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.

PubMed: 33711765
DOI: 10.1016/j.ejmech.2021.113309

実験手法

X-RAY DIFFRACTION (1.8 Å)