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