Discovery of New Quinolone-Based Diarylamides as Potent B-RAFV600E/C-RAF Kinase Inhibitors Endowed with Promising In Vitro Anticancer Activity

The emergence of cancer resistance to targeted therapy represents a significant challenge in cancer treatment. Therefore, identifying new anticancer candidates, particularly those addressing oncogenic mutants, is an urgent medical demand. A campaign of structural modifications has been conducted to further optimize our previously reported 2-anilinoquinoline-diarylamides conjugate VII as a B-RAFV600E/C-RAF inhibitor. Considering the incorporation of a methylene bridge between the terminal phenyl and cyclic diamine, focused quinoline-based arylamides have been tailored, synthesized, and biologically evaluated. Among them, the 5/6-hydroxyquinolines 17b and 18a stood out as the most potent members, with IC50 values of 0.128 mu M, 0.114 mu M against B-RAF(V600E), and 0.0653 mu M, 0.0676 mu M against C-RAF. Most importantly, 17b elicited remarkable inhibitory potency against the clinically resistant B-RAF(V600K) mutant with an IC50 value of 0.0616 mu M. The putative binding mode of 17b and 18a were studied by molecular docking and molecular dynamics (MD). Moreover, the antiproliferative activity of all target compounds has been examined over a panel of NCI-60 human cancer cell lines. In agreement with cell-free assays, the designed compounds exerted superior anticancer impact over the lead quinoline VII against all cell lines at a 10 mu M dose. Notably, both 17b and 18b showed highly potent antiproliferative activity against melanoma cell lines with growth percent under -90% (SK-MEL-29, SK-MEL-5, and UACC-62) at a single dose, while 17b maintained potency with GI(50) values of 1.60-1.89 mu M against melanoma cell lines. Taken together, 17b, a promising B-RAF(V600E/V600K) and C-RAF kinase inhibitor, may serve as a valuable candidate in the arsenal of anticancer chemotherapeutics.

Automated summary

The development of resistance to targeted therapy in cancer is a major challenge in cancer treatment. This study aimed to identify new anticancer candidates, especially those targeting oncogenic mutants. Through structural modifications, a series of tailored quinoline-based arylamides were synthesized and evaluated for their inhibitory potency against B-RAF and C-RAF kinases. Compound 17b emerged as the most potent and exhibited significant inhibitory activity against resistant B-RAF mutants. Molecular docking and molecular dynamics studies provided insights into the binding mode of 17b. Additionally, all target compounds showed superior anticancer activity compared to the lead compound in cell lines. Compound 17b demonstrated highly potent antiproliferative activity against melanoma cell lines. Therefore, 17b has the potential to be a valuable candidate for anticancer chemotherapy.