Design, Synthesis,\nand Antitumor Activity Evaluation\nof 2‑Phenylthiazole-5-Carboxylic Acid Derivatives Targeting\nTransactivation Response RNA-Binding Protein 2

Transactivation\nresponse (TAR) RNA-binding protein 2 (TRBP) plays\na critical role in microRNA (miRNA) biosynthesis, with aberrant expression\nlinked to various cancers. Previously, we identified <b>CIB-3b</b>, a phenyloxazole derivative that disrupts the TRBP-Dicer interaction\nin hepatocellular carcinoma (HCC). In this study, we optimized this\nscaffold and substituent, leading to the discovery of <b>CIB-L43</b>, a 2-phenylthiazole-5-carboxylic acid derivative with nanomolar\ninhibitory activity (EC<sub>50</sub> = 0.66 nM). <b>CIB-L43</b> demonstrated superior TRBP binding affinity (<i>K</i><sub><i>D</i></sub> = 4.78 nM) and enhanced disruption of TRBP-Dicer\ninteractions (IC<sub>50</sub> = 2.34 μM). Mechanistically, <b>CIB-L43</b> suppressed oncogenic miR-21 biosynthesis, increasing\nPTEN and Smad7 expression and inhibiting AKT and TGF-β signaling,\nthereby reducing HCC cell proliferation and migration. <i>In\nvivo</i>, <b>CIB-L43</b> exhibited favorable pharmacokinetics,\nincluding 53.9% oral bioavailability, and comparable antitumor efficacy\nto first-line anticancer drug, sorafenib, with lower toxicity. <b>CIB-L43</b> emerges as a promising HCC treatment candidate with\npotent TRBP inhibition and favorable drug-like properties.