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 NTRK 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 DZX19 (C02), 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, DZX19 induced G1 arrest, promoted apoptosis, and suppressed
TRK downstream signaling. DZX19 displayed excellent plasma
stability and moderate microsomal stability. In the Km-12 xenograft
model, DZX19 significantly suppressed tumor growth. These
results indicate that DZX19 serves as a novel TRK-targeting
lead compound for further investigation.