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

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F21%3A00541414" target="_blank" >RIV/61388963:_____/21:00541414 - isvavai.cz</a>
Alternative codes found
RIV/68378050:_____/21:00544833 RIV/61989592:15310/21:73610840 RIV/62690094:18470/21:50018115
Result on the web
<a href="https://doi.org/10.1016/j.ejmech.2021.113309" target="_blank" >https://doi.org/10.1016/j.ejmech.2021.113309</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.ejmech.2021.113309" target="_blank" >10.1016/j.ejmech.2021.113309</a>

Result language
angličtina
Original language name
Imidazo[1,2-c]pyrimidin-5(6H)-one inhibitors of CDK2: Synthesis, kinase inhibition and co-crystal structure
Original language description
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.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology

Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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