Novel phenylamino pyrimidine derivatives as potent and selective inhibitors of ABL1 tyrosine kinase for targeted anticancer therapy.

Phenyl amino pyrimidine (PAP) derivatives represent a promising scaffold in anticancer drug discovery due to their potential to selectively inhibit tyrosine kinase (TK) enzymes implicated in tumor progression. In the present study, we designed a focused ligand library using bioisosteric substitutions in the imatinib structure to improve its target affinity and pharmacokinetic properties. Molecular docking confirmed the high-affinity of the designed compounds against the human proto-oncogene tyrosine-protein kinase ABL1 (PDB ID: 2hyy), and eight potential leads were synthesized based upon their key interactions within the target's ATP-binding pocket. The synthetic routes for these molecules followed a robust multi-step protocol, yielding pure compounds characterized comprehensively by NMR, HRMS, and chromatographic analyses, confirming structural integrity and purity. Cellular cytotoxicity assays demonstrated potent antiproliferative effects of these derivatives against DLD-1, HCT-116, and HT-29 colorectal cancer cell lines, exhibiting superior efficacy and selectivity (SI) compared to the benchmark drug imatinib mesylate (IC50 = 18.3 μM; SI = 1.36). Based on docking score and experimental outcome in cell viability assays, two lead compounds DS37 (IC50 = 3.11 μM; SI > 16) and DS42 (IC50 = 11.9 μM; SI > 16.8) were selected for further validation through 100 ns molecular dynamics simulations for their mechanistic establishment with ABL1. These studies confirmed their stable binding modes and dynamic conformational compatibility with the TK active site.