Design and Characterization of a Natural Arf-GEFs Inhibitor Prodrug CHNQD-01255 with Potent Anti-Hepatocellular Carcinoma Efficacy In Vivo

作者：Yao-Yao Jiang, Yang Gao, Jianyu Liu, Ying Xu, Mei‐Yan Wei, Chang‐Yun Wang, Yu‐Cheng Gu, Chang‐Lun Shao · 发表于：Journal of Medicinal Chemistry · 年份：2022 · DOI：10.1021/acs.jmedchem.2c00532 · 被引用次数：22 · 研究领域：Cancer Mechanisms and Therapy、Peptidase Inhibition and Analysis、Enzyme function and inhibition

Brefeldin A (BFA), a well-known natural Arf-GEFs inhibitor, is effective against hepatocellular carcinoma (HCC), while the poor solubility, serious toxicity, and short half-life limit its potential. Herein, distinct corresponding prodrugs of BFA, including esters 1 – 15, carbonates 16 – 24 and 30 – 32, and carbamates 25 – 29, were synthesized and evaluated. CHNQD-01255 ( 16 ) with improved aqueous solubility (15–20 mg/mL) demonstrated favorable pharmacokinetic profiles. It behaved as expected by undergoing rapid conversion to BFA in vivo, and achieved sufficient high plasma exposure, prolonged half-life, as well as the improved bioavailability of BFA ( F = 18.96%). Meanwhile, CHNQD-01255 significantly suppressed tumor growth (TGI = 61.0%) at a dose of 45 mg/kg (p.o.) in the xenograft model. Notably, the improved safety profile of CHNQD-01255 (MTD > 750 mg/kg, p.o.) was confirmed to be superior to that of BFA (MTD < 506 mg/kg). Overall, CHNQD-01255 may serve as a safe and effective new anti-HCC prodrug.