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Imidazo[1,2-c]pyrimidin-5(6H)-one inhibitors of CDK2: Synthesis, kinase inhibition and co-crystal structure
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SYSNO ASEP 0541414 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Imidazo[1,2-c]pyrimidin-5(6H)-one inhibitors of CDK2: Synthesis, kinase inhibition and co-crystal structure Author(s) Jansa, J. (CZ)
Jorda, R. (CZ)
Škerlová, Jana (UOCHB-X) ORCID
Pachl, Petr (UOCHB-X) RID, ORCID
Peřina, M. (CZ)
Řezníčková, E. (CZ)
Heger, T. (CZ)
Gucký, T. (CZ)
Řezáčová, Pavlína (UOCHB-X) RID, ORCID
Lyčka, A. (CZ)
Kryštof, V. (CZ)Article number 113309 Source Title European Journal of Medicinal Chemistry. - : Elsevier - ISSN 0223-5234
Roč. 216, Apr 15 (2021)Number of pages 12 s. Language eng - English Country FR - France Keywords activity assay ; Co-crystal ; cyclin-dependent kinase 2 ; imidazo[1,2-c]pyrimidin-5(6H)-one ; ITC ; kinase inhibitor ; X-ray crystallography OECD category Biochemistry and molecular biology R&D Projects EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Limited access Institutional support UOCHB-X - RVO:61388963 UT WOS 000637742700018 EID SCOPUS 85102145194 DOI 10.1016/j.ejmech.2021.113309 Annotation 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. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Year of Publishing 2022 Electronic address https://doi.org/10.1016/j.ejmech.2021.113309
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