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

Article

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

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.

25 Aug 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of a Novel Small-Molecule Inhibitor Disrupting TRBP–Dicer Interaction against Hepatocellular Carcinoma via the Modulation of microRNA Biogenesis

Q1 · MEDICINE

Article

Author: Sheng, Yuwen ; Lu, Xiaoxia ; Wang, Tao ; He, Yujiao ; Wang, Fei ; Peng, Ting ; Yu, Jialing ; Liu, Wanli ; Li, Lingyu ; Zhao, Yongyun ; Zou, Jiawei ; Li, Sheng ; Yuan, Yi ; Peng, Huipan ; Ma, Xiaofang ; Hu, Kaifeng ; Zhang, Guolin ; Shi, Hailong ; Zhou, Zongyuan ; Li, Fu

MicroRNAs (miRNAs) are key players in human hepatocellular carcinoma (HCC) tumorigenesis. Therefore, small molecules targeting components of miRNA biogenesis may provide new therapeutic means for HCC treatment. By a high-throughput screening and structural simplification, we identified a small molecule, CIB-3b, which suppresses the growth and metastasis of HCC in vitro and in vivo by modulating expression profiles of miRNAome and proteome in HCC cells. Mechanistically, CIB-3b physically binds to transactivation response (TAR) RNA-binding protein 2 (TRBP) and disrupts the TRBP-Dicer interaction, thereby altering the activity of Dicer and mature miRNA production. Structure-activity relationship study via the synthesis of 45 CIB-3b derivatives showed that some compounds exhibited a similar inhibitory effect on miRNA biogenesis to CIB-3b. These results support TRBP as a potential therapeutic target in HCC and warrant further development of CIB-3b along with its analogues as a novel therapeutic strategy for the treatment of HCC.

22 Jul 2020·Chemistry – A European JournalQ2 · CHEMISTRY

Electrochemical Iodine‐Mediated Oxidation of Enamino‐Esters to 2H‐Azirine‐2‐Carboxylates Supported byDesign of Experiments

Q2 · CHEMISTRY

Article

Author: Babaoglu, Emre ; Hilt, Gerhard

AbstractAn electrochemical iodine‐mediated transformation of enamino‐esters for the synthesis of 2H‐azirine‐2‐carboxylates is presented. In addition, a thermic conversion of azirines to 4‐carboxy‐oxazoles in quantitative yield without purification was described. Both classes 2H‐azirines‐2‐carboxylates and the 4‐carboxy‐oxazoles are substructures in natural products and therefore are of considerable interest for synthetic and pharmaceutical chemists. The optimization was not performed in a conventional manner with a one‐factor‐at‐a‐time process but with aDesign of Experiments(DoE) approach. Beside a broad substrate scope the reaction was also employed to a robustness screen, a sensitivity assessment, and complemented with mechanistic considerations from cyclic voltammetry experiments.

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatocellular Carcinoma	Preclinical	China	Chengdu Institute of Biology, Chinese Academy of Sciences	13 Jun 2022

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