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

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/68378050:_____/21:00544833 RIV/61989592:15310/21:73610840 RIV/62690094:18470/21:50018115

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

1768-3254

Svazek periodika

216

Číslo periodika v rámci svazku

Apr 15

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

12

Strana od-do

113309

Kód UT WoS článku

000637742700018

EID výsledku v databázi Scopus

2-s2.0-85102145194