Li, N., Luo, C., Liu, Y., Duan, S., Wang, X., Cheng, H., Xue, D., Wang, Y., Li, W., Hou, S.X., Shao, L. (2025). Design, synthesis and biological evaluation of (E)-4-(2-((1H-indol-5-yl) methylene) hydrazineyl)-5,6,7,8-tetrahydropyrido [4',3':4,5] thieno[2,3-d] pyrimidine derivatives as Arf1-GEFs inhibitors for the treatment of colon cancer.  Eur. J. Med. Chem. 297(): 117962.

FBrf0263042

Research paper

Arf1, a member of the Ras superfamily of small GTPases, plays a crucial role in lipid metabolism, tumor progression, and immune suppression, making Arf1-GEFs inhibitors attractive targets for cancer immunotherapy. However, current Arf1 inhibitors face challenges such as high toxicity and poor solubility. In this study, we report the design, synthesis, and biological evaluation of a series of (E)-4-(2-((1H-indol-5-yl) methylene) hydrazineyl)-5,6,7,8-tetrahydropyrido [4',3':4,5] thieno[2,3-d] pyrimidine derivatives, derived from the lead compound Du102. Rational structural modifications significantly enhanced aqueous solubility while retaining strong Arf1 inhibitory activity. Among these, 18a emerged as a potent Arf1-GEFs inhibitor, effectively promoting CCL5 expression, exhibiting improved in vitro pharmacokinetic properties and demonstrating robust antitumor efficacy in CT26 colon cancer xenograft models. This study identifies 18a as a promising candidate for colon cancer immunotherapy and provides a solid foundation for the development of novel Arf1-GEFs inhibitors with superior pharmacological properties.