Von Hippel-Lindau syndrome (VHL) is a component of the protein complex that includes elongin B, elongin C, and cullin-2, and possesses ubiquitin ligase E3 activity. VHL can induces hypoxia inducible factor (HIF) ubiquitination and degradation. VH-298 is a potent inhibitor of the VHL with a Kd of 90 nM as determined by isothermal titration calorimetry and 80 nM in a competitive fluorescence polarization assay. In vitro, the measured permeability of VH298 was 19.4 nm/s, and 500 μM of VH-298 did not affect the viability of HCC, Hela, RCC4-HA, RCC40-HA-VHL, U2OS and CTL cell lines, suggesting that VH298 was permeable and not toxic to cells. Treatment with 1 – 250 μM VH-298 for 2 hour induced dose-dependent accumulation of HIF-1α levels in Hela cells. In addition, VH-298 induced detectable HIF activity at concentration of 10 μM. Treatment with 100 μM VH298 elicited a HIF-dependent hypoxic response in HFF, Hela, and U2OS lines[3]. In addition, VH-298 promoted rat fibroblasts proliferation at concentration of 30 μM and 100 μM, while 10 μM and 200 μM had no significant effect on cell proliferation. Treatment with 20 μM VH-298 promoted the tubule formation of HUVECs, however, 100 μM and 200 μM of VH-298 disturbed the tubule formation of HUVECs. In vivo, administered 100 μL of 30 μM VH-298 via local injection every three days accelerated wound healing in Rats with DM[4].
作用机制
VH-298 stabilizes HIF-α and induces a hypoxic response to block VHL-HIFα interaction[3].
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