Development of New N-{4-[(7-Chloro-5-methylpyrrolo[2,1-f] [1,2,4]triazin-4-yl)oxy]-3-fluorophenyl}benzenesulfonamide Analogues: Exploring Anticancer Potential through MerTK Inhibition

Abstract

Mer proto-oncogene tyrosine-protein kinase (MerTK), a part of TAM (TYRO3, AXL and MerTK) family, is directly correlated with metastasis and various types of cancers. The inhibition of this receptor tyrosine kinase is one of the promising therapeutic strategies, as chemotherapy has higher efficacy. Considering the pharmacophoric features of the active domain of MerTK and structural characteristics of investigational drug, BMS794833, we have designed new N-(4-((7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy)-3-fluorophenyl)benzenesulfonamide analogues (BDS-001 to BDS-005). In cytotoxic studies, BDS-001 displayed significantly higher cytotoxicity than cisplatin. It showed IC50 values of 2.09 µM, 1.96 µM and 3.08 µM against A549, MCF-7 and MDA-MB-231 cancer cell lines, respectively. In DMPK studies, BDS-001 was most stable and displayed moderate MerTK inhibitory potential. Molecular docking studies were performed to corroborate the MerTK inhibition, and BDS-001 was gave the most significant docking score (-12.33 Kcal/mol). Docking interactions demonstrated that imine and amine group of 3-chloropyridine moiety of BMS794833 formed a hydrogen bond with main chain of ATP pocket residue Met674, while oxygen atoms of 4-oxo-1,4-dihydropyridine-3-carboxamide moiety established hydrogen bonds with Lys619 and Asp741 amino acid residues of allosteric pocket of MerTK protein. These promising results are evident that N-(4-((7-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)oxy)-3-fluorophenyl)benzenesulfonamide pharmacophore can provide potential insights in development of new MerTK inhibitors.