贝投体育8059:Design, Synthesis, and Antitumor Activity Evaluation of 2-Phenylthiazole-5-Carboxylic Acid Derivatives Targeting Transactivation Response RNA-Binding Protein 2
稿件作者：Shi H, Yu J, Li L, Ji M, Li R, Peng T, Cheng Y, Wang T, Yang L, Wu Z, Zhang G, Wang F, Lu X
通讯作者：Wang F, Lu X
刊物名称：Journal of Medicinal Chemistry
发表年份：2025
卷：68
期：1
页码：421-447
影响因子：
文章摘要：
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.
