SU5416

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Background

Description: SU5416 was found to inhibit VEGF-dependent phosphorylation of the Flk-1 receptor in Flk-1-overexpressing NIH 3T3 cells with an IC50 of 1.04±0.53 mM Vascular endothelial growth factor (VEGF), which stimulates vasculogenesis and angiogenesis, is able to create new blood vessels during embryonic development, new blood vessels after injury, muscle following exercise, and new vessels (collateral circulation) to bypass blocked vessels. Semaxanib (SU5416), a tyrosine-kinase inhibitor drug designed by SUGEN as a cancer therapeutic, is a potent and selective synthetic inhibitor of the Flk-1/KDR VEGF receptor tyrosine kinase demonstrating antiangiogenic effects.Preclinical study: SU5416 was found to inhibit vascular endothelial growth factor-dependent mitogenesis of human endothelial cells. Moreover, systemic administration of SU5416 at nontoxic doses in mice resulted in the inhibition of subcutaneous tumor growth of cells derived from various tissue origins. The antitumor effect of SU5416 was accompanied by the appearance of pale white tumors, supporting its antiangiogenic property [1]. Another study showed that SU5416 was also an aryl hydrocarbon receptor (AHR) agonist with unique properties. Like TCDD, SU5416 favors induction of indoleamine 2,3 dioxygenase (IDO) in immunologically relevant populations such as dendritic cells in an AHR-dependent manner, leading to generation of regulatory T-cells in vitro. These characteristics lead us to suggest that SU5416 may be an ideal clinical agent for treatment of autoimmune diseases and prevention of transplant rejection, two areas where regulatory ligands of the AHR have shown promise [2].Clinical trial: As an anticancer agent, SU5416 went as far as Phase III clinical trials, but showed poor results. Its clical termination is based on the results from a planned interim efficacy and safety analyses of a large phase III study of standard chemotherapy with or without SU5416 in the treatment of patients with advanced stage colorectal cancer, which shows that the study will not achieve the defined trial endpoints due to a lack of clinical benefit.

[1] Fong TA, Shawver LK, Sun L, Tang C, App H, Powell TJ, Kim YH, Schreck R, Wang X, Risau W, Ullrich A, Hirth KP, McMahon G. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res. 1999;59(1):99-106.
[2] Mezrich JD, Nguyen LP, Kennedy G, Nukaya M, Fechner JH, Zhang X, Xing Y, Bradfield CA. SU5416, a VEGF receptor inhibitor and ligand of the AHR, represents a new alternative for immunomodulation. PLoS One. 2012;7(9):e44547. doi: 10.1371/journal.pone.0044547.