Development of quinoline derivatives as dual EGFR/HDAC-2 inhibitors: design, synthesis, anticancer evaluation, and molecular dynamics simulations

Abstract The quinoline scaffold is widely exploited in the design of new anticancer candidates. As a continuation of our previous work in the search for promising anticancer candidates, we designed novel quinoline-based compounds linked to a range of heterocyclic rings by applying a molecular hybridization strategy. In this work, the resulting quinoline derivatives were synthesized and evaluated for their anti-proliferative activity against three cancer cell lines, namely PC-3, HCT-116, and MDA-MB-231, in addition to one normal cell line, WI-38. Among these compounds, two derivatives ( 4) and (11) showed potent anti-proliferative activity against MDA-MB-231 breast cancer cells with IC₅₀ values of 4.91 and 8.25 µ M, respectively. The same two derivatives also showed significant activity against the HCT-116 colon cancer cell line with IC₅₀ values of 6.38 and 9.44 µ M, respectively. Mechanistic studies further showed that compound (4) potently inhibited EGFR WT (IC₅₀ = 0.084 µ M) and mutant EGFR forms, as well as HDAC-2 with IC 50 = 0.123 µ M. All biological assays were performed in three independent experiments ( n = 3), and all reported differences versus the untreated control were significant at a two-sided adjusted P < 0.05. Additionally, western blot analysis of compound (4) revealed downregulation of pEGFR, pERK, and pAKT, while RT-qPCR analysis showed upregulation of BAX and caspase-3, -7, and − 9 and downregulation of BCL-2 at the mRNA level. Cell-cycle analysis showed that derivative (4) induced arrest at the G 1 /S boundary. Taken together, all these results, along with molecular docking and molecular dynamics simulations, supported the stable binding within the ATP-binding site of EGFR and the zinc-binding pocket of HDAC-2.