Discovery of a Highly Potent and Selective MYOF Inhibitor with Improved Water Solubility for the Treatment of Gastric Cancer
Discovery of a Highly Potent and Selective MYOF Inhibitor with Improved Water Solubility for the Treatment of Gastric Cancer
复制标题
DOI：
10.1021/acs.jmedchem.3c01639
复制
发表时间：
2023-12-06
影响因子：
7.3
通讯作者：
Chen，Yihua
中科院分区：
文献类型：
--
作者：
Gu，Haijun;Zhang，Ting;Chen，Yihua
Myoferlin（MYOF）通过调节胞吐和胞吞作用介导多种癌症的生长和转移，作为新兴的治疗靶点。然而，先前报道的MYOF抑制剂6 y在临床前研究中由于其不良的物理化学性质（例如水溶性）而未能成为有利的候选药物。自然，基于先导化合物6 y合成并优化了一系列新型MYOF抑制剂。优化化合物HJ 445 A对胃癌细胞MGC 803和MKN 45的IC_（50）分别为0.16和0.14 μM。此外，HJ 445富含MYOF-C2 D结构域，aKD为0.17 μM，HJ 445 A通过逆转上皮-间质转化（EMT）过程阻止胃癌细胞迁移，并以浓度依赖方式抑制MKN 45细胞的殖民地形成。值得注意的是，与6 y相比，HJ 445 A的水溶性显著提高，提高了约170倍。此外，HJ 445 A在体内也表现出上级抗肿瘤作用。
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 compound6y. The optimal compoundHJ445Apotently repressed the proliferation of gastric cancer cells with IC50values of 0.16 and 0.14 μM in MGC803 and MKN45, respectively. Moreover,HJ445Abound to the MYOF-C2D domain with aKDof 0.17 μM, andHJ445Aprevented 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 ofHJ445Awas significantly improved compared to6y, with about 170-fold enhancement. Additionally,HJ445Aalso demonstrated superior antitumor efficacyin vivo.