Targeting CDK2 and CDK7: rational design of pyrazolo[1,5-a]pyrimidine derivatives as potent anticancer agents

Abstract

A series of novel pyrazolo[1,5-a]pyramidal derivatives have been developed based on structural analysis of previously identified CDK2 inhibitors. Biological screening revealed that the target compounds were moderate compared to potent anticancer agents. Furthermore, the safety of the prospective analogues was demonstrated by their low cytotoxicity to normal human cells. Screening of the most active compounds against CDK2 enzymes revealed that compounds 5i and 5j (IC₅₀ = 0.25 and 0.16 μM, respectively) were the best CDK2 inhibitors with comparable or higher potency than roscovitine (IC₅₀ = 0.24 μM). In addition, both analogues showed potent activity against CDK7 (IC₅₀ = 0.12 and 0.14 μM, respectively). It was found that compounds 5i and 5j inhibited cell division during the S phase of the cell cycle and then induced apoptosis. In addition, they induced apoptosis by raising the levels of p53 and Bax protein expression while reducing the amount of Bcl-2. As expected, the molecular docking simulations have shown that these compounds can form stable complexes with different interactions that can match the binding site of CDK2.