Imidazo[1,2-c]pyrimidin-5(6H)-one inhibitors of CDK2: Synthesis, kinase inhibition and co-crystal structure.
Eur J Med Chem
; 216: 113309, 2021 Apr 15.
Article
in En
| MEDLINE
| ID: mdl-33711765
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrimidines
/
Protein Kinase Inhibitors
/
Cyclin-Dependent Kinase 2
/
Imidazoles
Limits:
Humans
Language:
En
Journal:
Eur J Med Chem
Year:
2021
Document type:
Article
Affiliation country:
Czech Republic