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

0541414 - ÚOCHB 2022 RIV FR eng J - Článek v odborném periodiku
Jansa, J. - Jorda, R. - Škerlová, Jana - Pachl, Petr - Peřina, M. - Řezníčková, E. - Heger, T. - Gucký, T. - Řezáčová, Pavlína - Lyčka, A. - Kryštof, V.
Imidazo[1,2-c]pyrimidin-5(6H)-one inhibitors of CDK2: Synthesis, kinase inhibition and co-crystal structure.
European Journal of Medicinal Chemistry. Roč. 216, Apr 15 (2021), č. článku 113309. ISSN 0223-5234. E-ISSN 1768-3254
Grant CEP: GA MŠMT(CZ) EF16_019/0000729
Institucionální podpora: RVO:61388963
Klíčová slova: activity assay * Co-crystal * cyclin-dependent kinase 2 * imidazo[1,2-c]pyrimidin-5(6H)-one * ITC * kinase inhibitor * X-ray crystallography
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 7.088, rok: 2021
Způsob publikování: Omezený přístup
https://doi.org/10.1016/j.ejmech.2021.113309

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.
Trvalý link: http://hdl.handle.net/11104/0318978