Xg-13, a derivate of marine natural product, exhibits anti-angiogenesis ability in hepatocellular carcinoma via inhibiting Axl signaling pathway.

Angiogenesis plays a crucial role in tumor development, particularly in hepatocellular carcinoma (HCC), which is characterized by rapid progression due to abundant vascularization. The key processes associated with angiogenesis include endothelial cell growth, migration, invasion, and tube formation. Therefore, anti-angiogenesis represents an effective strategy for tumor therapy. In our previous research, we isolated the marine natural product Cryptoechinuline D (Cry D) from the soft coral-associated Aspergillus sp., and subsequently modified it to generate several anti-tumor derivatives with enhanced activity. One of the derivatives, 3-formyl-4-hydroxy-2-((E)-2-((7S,10R,Z)-10-methyl-3-((2-(2-methylbut-3-en-2-yl)-1H-indol-3-yl)methylene)-2,5-dioxo-1,4-diazaspiro[5.5]undec-8-en-7-yl)vinyl)-5-(3-methylbut-2-en-1-yl)phenyl acetate (also named Xg-13) exhibits significant pharmacological effects, including the inhibition of endothelial cell growth, migration, invasion, and tube formation, by blocking the activation of the Axl signaling pathway. Notably, molecular docking studies revealed that Xg-13 binds strongly to Axl, a finding confirmed by drug affinity responsive target stability assay and molecular dynamics, which further supports its potential as a promising Axl inhibitor. Furthermore, Xg-13 significantly decreased neovascularization in Huh7 xenografts, resulting in tumor growth inhibition. In conclusion, our findings suggest that Xg-13 is a promising novel anti-angiogenic agent for HCC therapy.