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
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.