化学
体内
溶解度
内吞作用
癌症
胞吐
癌细胞
IC50型
癌症研究
转移
体外
药理学
生物物理学
生物化学
分泌物
受体
内科学
生物
生物技术
有机化学
医学
作者
Haijun Gu,Ting Zhang,Tian Guan,Min Wu,Li Shen,Yunqi Li,Mengmeng Guo,Shouxin Zhang,Yangrui Peng,Dazhao Mi,Mingyao Liu,Zhengfang Yi,Yihua Chen
标识
DOI:10.1021/acs.jmedchem.3c01639
摘要
Myoferlin (MYOF) mediates the growth and metastasis of various cancers as an emerging therapeutic target by regulating exocytosis and endocytosis. However, the previously reported MYOF inhibitor, 6y, failed to be a favorable candidate agent due to its poor physicochemical properties, such as water solubility, in preclinical studies. Naturally, a novel range of MYOF inhibitors was synthesized and optimized based on the lead compound 6y. The optimal compound HJ445A potently repressed the proliferation of gastric cancer cells with IC50 values of 0.16 and 0.14 μM in MGC803 and MKN45, respectively. Moreover, HJ445A bound to the MYOF-C2D domain with a KD of 0.17 μM, and HJ445A prevented the migration of gastric cancer cells by reversing the epithelial–mesenchymal transition (EMT) process and inhibited the colony formation of the MKN45 cells in a concentration-dependent manner. Notably, the water solubility of HJ445A was significantly improved compared to 6y, with about 170-fold enhancement. Additionally, HJ445A also demonstrated superior antitumor efficacy in vivo.
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