Discovery of a Novel Phenyl Thiophene-3-carboxamide Derivative DZX19 as an Orally TRK Inhibitor with Potent Antitumor Effects

Tropomyosin receptor kinase (TRK) is an important therapeutic target for tumors driven by <i>NTRK</i> gene fusions. However, the clinically approved TRK inhibitors, including Larotrectinib and Entrectinib, are limited by insufficient efficacy and resistance due to kinase mutations. Here, we report <b>DZX19</b> (<b>C02</b>), a novel phenyl thiophene-3-carboxamide TRK inhibitor developed via a pharmacophore-guided scaffold-hopping approach combined with structure-based design, based on the key binding features of Entrectinib. DZX19 demonstrated stronger in vitro activity and an improved resistance profile against Entrectinib-resistant TRKA mutants, including G595R, F589L, and G667C. In the TPM3-NTRK1 fusion-positive Km-12 cell line, <b>DZX19</b> induced G1 arrest, promoted apoptosis, and suppressed TRK downstream signaling. <b>DZX19</b> displayed excellent plasma stability and moderate microsomal stability. In the Km-12 xenograft model, <b>DZX19</b> significantly suppressed tumor growth. These results indicate that <b>DZX19</b> serves as a novel TRK-targeting lead compound for further investigation.