Design, Synthesis, and Antiproliferative Activity of New 5-Chloro-indole-2-carboxylate and Pyrrolo[3,4-]indol-3-one Derivatives as Potent Inhibitors of EGFR/BRAF Pathways.

Mutant EGFR/BRAF pathways are thought to be crucial targets for the development of anticancer drugs since they are over-activated in several malignancies. We present here the development of a novel series of 5-chloro-indole-2-carboxylate , and pyrrolo[3,4-]indol-3-ones derivatives as potent inhibitors of mutant EGFR/BRAF pathways with antiproliferative activity. The cell viability assay results of , , and revealed that none of the compounds tested were cytotoxic, and that the majority of those tested at 50 µM had cell viability levels greater than 87%. Compounds , , and had significant antiproliferative activity with GI values ranging from 29 nM to 78 nM, with outperforming and in their inhibitory actions against the tested cancer cell lines. Compounds were tested for EGFR inhibition, with IC values ranging from 68 nM to 89 nM. The most potent derivative was found to be the -piperidinyl derivative (R = -piperidin-1-yl), with an IC value of 68 nM, which was 1.2-fold more potent than erlotinib (IC = 80 nM). Interestingly, all the tested compounds had higher anti-BRAF activity than the reference erlotinib but were less potent than vemurafenib, with compound having the most potent activity. Moreover, compounds and showed an 8-fold selectivity index toward EGFR protein over wild-type. Additionally, molecular docking of and against BRAF and EGFR enzymes revealed high binding affinity and active site interactions compared to the co-crystalized ligands. The pharmacokinetics properties (ADME) of revealed safety and good pharmacokinetic profile.