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 3a–e, 4a–c and pyrrolo[3,4-b]indol-3-
ones 5a–c derivatives as potent inhibitors of mutant EGFR/BRAF pathways with antiproliferative
activity. The cell viability assay results of 3a–e, 4a–c, and 5a–c revealed that none of the compounds
tested were cytotoxic, and that the majority of those tested at 50 M had cell viability levels greater
than 87%. Compounds 3a–e, 4a–c, and 5a–c had significant antiproliferative activity with GI50 values
ranging from 29 nM to 78 nM, with 3a–e outperforming 4a–c and 5a–c in their inhibitory actions
against the tested cancer cell lines. Compounds 3a–e were tested for EGFR inhibition, with IC50
values ranging from 68 nM to 89 nM. The most potent derivative was found to be the m-piperidinyl
derivative 3e (R = m-piperidin-1-yl), with an IC50 value of 68 nM, which was 1.2-fold more potent
than erlotinib (IC50 = 80 nM). Interestingly, all the tested compounds 3a–e had higher anti-BRAFV600E
activity than the reference erlotinib but were less potent than vemurafenib, with compound 3e having
the most potent activity. Moreover, compounds 3b and 3e showed an 8-fold selectivity index toward
EGFRT790M protein over wild-type. Additionally, molecular docking of 3a and 3b against BRAFV600E
and EGFRT790M enzymes revealed high binding affinity and active site interactions compared to the
co-crystalized ligands. The pharmacokinetics properties (ADME) of 3a–e revealed safety and good
pharmacokinetic profile