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

Hailong Shi; Jialing Yu; Lingyu Li; Minghui Ji; Runze Li; Ting Peng; Yao Cheng; Tao Wang; Linhan Yang; Zhao Wu; Guolin Zhang; Fei Wang; Xiaoxia Lu

doi:10.1021/acs.jmedchem.4c02041

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

J Med Chem. 2024 Dec 26. doi: 10.1021/acs.jmedchem.4c02041. Online ahead of print.

Authors

Hailong Shi^{1

2}, Jialing Yu^{1

2}, Lingyu Li^{1

2}, Minghui Ji^{1

2}, Runze Li³, Ting Peng^{1

4}, Yao Cheng^{1

2}, Tao Wang^{1

2}, Linhan Yang^{1

2}, Zhao Wu^{1

2}, Guolin Zhang¹, Fei Wang¹, Xiaoxia Lu¹

Affiliations

¹ Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
² University of Chinese Academy of Sciences, Beijing 100049, China.
³ Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 611731, China.
⁴ Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, China.

PMID: 39722648
DOI: 10.1021/acs.jmedchem.4c02041

Abstract

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 (K_D = 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.