Design, Synthesis, and Antitumor Activity Evaluation of 2-Phenylthiazole-5-Carboxylic Acid Derivatives Targeting Transactivation Response RNA-Binding Protein 2.

Transactivation response (TAR) RNA-binding protein 2 (TRBP) plays a critical role in microRNA (miRNA) biosynthesis, with aberrant expression linked to various cancers. Previously, we identified , a phenyloxazole derivative that disrupts the TRBP-Dicer interaction in hepatocellular carcinoma (HCC). In this study, we optimized this scaffold and substituent, leading to the discovery of , a 2-phenylthiazole-5-carboxylic acid derivative with nanomolar inhibitory activity (EC = 0.66 nM). demonstrated superior TRBP binding affinity ( = 4.78 nM) and enhanced disruption of TRBP-Dicer interactions (IC = 2.34 μM). Mechanistically, suppressed oncogenic miR-21 biosynthesis, increasing PTEN and Smad7 expression and inhibiting AKT and TGF-β signaling, thereby reducing HCC cell proliferation and migration. , exhibited favorable pharmacokinetics, including 53.9% oral bioavailability, and comparable antitumor efficacy to first-line anticancer drug, sorafenib, with lower toxicity. emerges as a promising HCC treatment candidate with potent TRBP inhibition and favorable drug-like properties.