Design, synthesis and biological study of novel pyrido[2,3-d]pyrimidine as anti-proliferative CDK2 inhibitors

The design and synthesis of a small library of 4-aminopyrido[2,3-d]pyrimidine derivatives is reported. The potential activity of these compounds as CDK2/Cyclin A, CDK4/Cyclin D, EGFR and anti-tumor was evaluated by cytotoxicity studies in A431a, SNU638b, HCT116 and inhibition of CDK2-Cyclin A, CDK4/Cyclin D and EGFR enzyme activity in vitro. The anti-proliferative and CDK2-Cyclin A inhibitory activity of compounds 4c and 11a was significantly more active than roscovotine with IC50 0.3 and 0.09 μM respectively. Molecular modeling study, including fitting to a 3D-pharmacophore model, docking into cyclin dependant kinase2 (CDK2) active site and binding energy calculations were carried out and these studies suggested the same binding orientation inside the CDK2 binding pocket for these analogs compared to ATP.

A library of novel pyrido[2,3-d]pyrimidines were fitted to 3D-pharmacophore model and docked into CDK2 active site then the promising compounds were synthesized. CDK2/cyclin A, EGFR inhibition activities and anti-tumor activity were tested.Figure optionsDownload as PowerPoint slideHighlights
► 3D-Pharmacophore and Docking were used to select the promising compounds.
► A series of novel pyrido[2,3-d]pyrimidines were synthesized.
► CDK2, EGFR and anti-proliferative activities were evaluated.
► Compounds 11a and 4c were the most potent against CDK2.
► Modification at C2 with short chain substituent can increase biologic activity.