Design, synthesis and biological evaluation of novel 1H-indole-3-carbonitrile derivatives as potent TRK Inhibitors

Abstract

Tropomyosin receptor kinase (TRK) has emerged as a promising therapeutic target in cancers driven by NTRK gene fusions. Herein, we report a highly potent TRK inhibitor, C11, developed using bioisosteric replacement and computer-aided drug design (CADD) strategies. Compound C11 demonstrated significant antiproliferative effects against TRK-dependent cell lines (Km-12), and exhibited a dose-dependent inhibition of both colony formation and cell migration. Mechanistic study revealed that C11 induced cancer cell death by arresting the cell cycle, triggering apoptosis, and reducing phosphorylated TRK levels. In vitro stability assays showed that compound C11 possessed excellent plasma stability (t_1/2 > 480 min) and moderate liver microsomal stability (t_1/2 = 38.9 min). Pharmacokinetic evaluation further indicated an oral bioavailability of 15.2% for compound C11. These results highlight compound C11 as a promising lead compound for the further development of TRK inhibitors.