Design, Synthesis, and Anti-Proliferative Action of Purine/Pteridine-Based Derivatives as Dual Inhibitors of EGFR and BRAFV600E

The investigation of novel EGFR and BRAF(V600E) dual inhibitors is intended to serve as targeted cancer treatment. Two sets of purine/pteridine-based derivatives were designed and synthesized as EGFR/BRAF(V600E) dual inhibitors. The majority of the compounds exhibited promising antiproliferative activity on the cancer cell lines tested. Compounds 5a, 5e, and 7e of purine-based and pteridine-based scaffolds were identified as the most potent hits in anti-proliferative screening, with GI(50) values of 38 nM, 46 nM, and 44 nM, respectively. Compounds 5a, 5e, and 7e demonstrated promising EGFR inhibitory activity, with IC50 values of 87 nM, 98 nM, and 92 nM, respectively, when compared to erlotinib's IC50 value of 80 nM. According to the results of the BRAF(V600E) inhibitory assay, BRAF(V600E) may not be a viable target for this class of organic compounds. Finally, molecular docking studies were carried out at the EGFR and BRAF(V600E) active sites to suggest possible binding modes.