Discovery of a Highly Potent and Selective MYOF Inhibitor with Improved Water Solubility for the Treatment of Gastric Cancer

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 mu M in MGC803 and MKN45, respectively. Moreover, HJ445A bound to the MYOF-C2D domain with a K-D of 0.17 mu M, 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.