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

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 GI₅₀ 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.