Molecular docking, DFT and antiproliferative properties of 4‐(3,4‐dimethoxyphenyl)−3‐(4‐methoxyphenyl)−1‐phenyl‐1H‐pyrazolo[3,4‐b]pyridine as potent anticancer agent with CDK2 and PIM1 inhibition potency

Abstract Due to the limited effeteness and safety concerns associated with current cancer treatments, there is a pressing need to develop novel therapeutic agents. 4‐(3,4‐Dimethoxyphenyl)−3‐(4‐methoxyphenyl)−1‐phenyl‐1 H ‐pyrazolo[3,4‐ b ]pyridine ( 3 ) was synthesized and Initially screened on 59 cancer cell lines showed promising anticancer activity, so, it was chosen for a 5‐dose experiment by the NCI/USA. The GI 50 values ranged from 1.04 to 8.02 μM on the entire nine panels (57 cell lines), with a GI 50 of 2.70 μM for (MG‐MID) panel, indicating an encouraging action. To further explore the molecular attributes of compound 3 , we optimized its structure using DFT with the B3LYP/6‐31 + + G(d,p) basis set. We have considered vibrational analysis, bond lengths and angles, FMOs, and MEP for the structure. Additionally, pharmacokinetic assessments were conducted using various in‐silico platforms to evaluate the compound safety. A molecular modeling study created a kinase profile on 44 different kinases. This allowed us to study our compound's binding affinity to these kinases and compare it to the co‐crystallized one. Our findings revealed compound 3 exhibited better binding for half of the tested kinases, suggesting its potential as a multi‐kinase inhibitor. To further validate our computational results, we tested compound 3 for its inhibitory effects on CDK2 and PIM1. Compound 3 exhibited an IC 50 of 0.30 µM for CDK2 inhibition, making it five times less active than Roscovitine, which has an IC 50 of 0.06 µM. However, compound 3 demonstrated slightly better inhibition of PIM1 compared to Staurosporine. These findings suggest that compound 3 is a promising anticancer agent with the potential for further development into a highly active compound.