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 <b>CIB-3b</b>, 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 <b>CIB-L43</b>, a 2-phenylthiazole-5-carboxylic acid derivative with nanomolar inhibitory activity (EC₅₀ = 0.66 nM). <b>CIB-L43</b> demonstrated superior TRBP binding affinity (<i>K</i>_<i>D</i> = 4.78 nM) and enhanced disruption of TRBP-Dicer interactions (IC₅₀ = 2.34 μM). Mechanistically, <b>CIB-L43</b> suppressed oncogenic miR-21 biosynthesis, increasing PTEN and Smad7 expression and inhibiting AKT and TGF-β signaling, thereby reducing HCC cell proliferation and migration. <i>In vivo</i>, <b>CIB-L43</b> exhibited favorable pharmacokinetics, including 53.9% oral bioavailability, and comparable antitumor efficacy to first-line anticancer drug, sorafenib, with lower toxicity. <b>CIB-L43</b> emerges as a promising HCC treatment candidate with potent TRBP inhibition and favorable drug-like properties.