02836nas a2200325   4500008004100000022001400041245019000055210006900245260000800314300001200322490000700334520169300341653002902034653002202063653002202085653002102107653001702128100002802145700002502173700001802198700002602216700002702242700002002269700001802289700002402307700002302331700002802354700001902382856010902401       2025                        eng d  a0936-521400aDevelopment 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 inhibition0 aDevelopment of new N 47Chloro5methylpyrrolo21f 124triazin4yloxy3  cMAR  a522-5300 v363 a<p>
	Mer proto-oncogene tyrosine-protein kinase (MerTK), a part of the TAM (TYRO3, AXL, and MerTK) family, is directly correlated with metastasis and various types of cancers. The inhibition of this receptor is a promising strategy for more-effective chemotherapy. Considering the pharmacophoric features of the active domain of MerTK and the structural characteristics of the investigational drug BMS794833, we designed five new N -{4-[(7-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)oxy]-3-fluorophenyl}benzenesulfonamide analogues. In cytotoxicity studies, one of the analogues displayed a significantly higher cytotoxicity than cisplatin. It showed IC50 values of 2.09, 1.96, and 3.08 mu M against A549, MCF-7, and MDA-MB-231 cancer cell lines, respectively. In drug metabolism and pharmacokinetic studies, it was the most stable analogue and displayed a moderate MerTK inhibitory potential. Molecular-docking studies were performed to corroborate the MerTK inhibition, and the same analogue achieved the most significant docking score (-12.33 kcal/mol). Docking interactions demonstrated that the imine and amine group of the 3-chloropyridine moiety of BMS794833 formed hydrogen bonds with the main chain of the ATP pocket residue Met674, while the oxygen atoms of the 4-oxo-1,4-dihydropyridine-3-carboxamide moiety established hydrogen bonds with the Lys619 and Asp741 amino acid residues of the allosteric pocket of MerTK protein. These promising results provide evidence that the N -{4-[(7-chloro-5-methylpyrrolo[2,1- f ][1,2,4]triazin-4-yl)oxy]-3-fluorophenyl}benzenesulfonamide pharmacophore can give potential insights into the development of new MerTK inhibitors.</p>
10acancer chemotherapeutics10akinase inhibitors10ametabolic studies10apyrrolotriazines10asulfonamides1 aSathe, Balaji, Dashrath1 aMeenakshi, Meenakshi1 aMurti, Yogesh1 aMane, Madhav, Shivaji1 aPandey, Sarvesh, Kumar1 aMahajan, Shriya1 aRawat, Pramod1 aKandhari, Harsimrat1 aGoel, Kapil, Kumar1 aDwivedi, Ashish, Ranjan1 aRathod, S., V.  uhttps://library.ncl.res.in/content/development-new-n-4-7-chloro-5-methylpyrrolo21-f-124triazin-4-yloxy-3