Novel artemisinin derivative FO8643 with anti-angiogenic activity inhibits growth and migration of cancer cells via VEGFR2 signaling

The vascular endothelial growth factor receptor 2 (VEGFR2) is widely recognized as a key effector in angiogenesis and cancer progression and has been considered a critical target for the development of anti-cancer drugs. Artemisinin (ARS) and its derivatives exert profound efficacy in treating not only malaria but also cancer. As a novel ARS-type compound, FO8643 caused significant suppression of the growth of a panel of cancer cells, including both solid and hematologic malignancies. In CCRF-CEM leukemia cells, FO8643 dramatically inhibited cell proliferation coupled with increased apoptosis and cell cycle arrest. Additionally, FO8643 restrained cell migration in the 2D wound healing assay as well as in a 3D spheroid model of human hepatocellular carcinoma HUH-7 cells. Importantly, SwissTargetPrediction predicted VEGFR2 as an underlying target for FO8643. Molecular docking simulation further indicated that FO8643 formed hydrogen bonds and hydrophobic interactions within the VEGFR2 kinase domain. Moreover, FO8643 directly inhibited VEGFR2 kinase activity and its downstream action including MAPK and PI3K/Akt signaling pathways in HUH-7 cells. Encouragingly, FO8643 decreased angiogenesis in the chorioallantoic membrane assay in vivo. Collectively, FO8643 is a novel ARS-type compound exerting potential VEGFR2 inhibition. FO8643 may be a viable drug candidate in cancer therapy.