生物活性

• 描述Phospholipase D (PLD) is an essential enzyme responsible for the production of the lipid second messenger phosphatidic acid. This class of enzymes may play a role in numerous cellular pathways, including signal transduction, membrane trafficking, and the regulation of mitosis. PLD1 and PLD2 are the two reported mammalian isoforms of PLD. PLD1 has low basal activity that is highly regulated by protein kinase C (PKC), Arf and Rho GTPases, whereas PLD2 has high basal activity and mediates a number of unique protein interactions. VU-0155069 (also termed CAY10593) is a PLD1 selective inhibitor. Based on an enzyme activity assay, the inhibitory IC₅₀s of VU-0155069 against PLD1 and PLD2 are 46 nM and 933 nM, respectively. Alternatively, in cellular systems, the inhibitory IC₅₀s of VU-0155069 against PLD1 and PLD2 are 11 nM and 1800 nM, respectively. In transwell invasion assays performed in MDA-MB-231, 4T1 or PMT cells, three well characterized highly metastatic breast cancer cell lines, VU-0155069 was tested at the concentration of 0.2 μM or 20 μM. The results indicated that both concentrations of VU-0155069 significantly inhibited migration of the three cell lines. According to another report in the setting of isolated rheumatoid arthritis synovial fibroblast (RASF) cells cultured in vitro, 10 μM VU-0155069 inhibited IL-6 mRNA level by ~25% in the stimulation of IL-17 and TNFα and also obviously suppressed IL-6 secretion when TNFα was applied as a single stimulus.

• 动物研究
  剂量	Mice: 2.7 mg/kg[1] (i.p.); 10 mg/kg[2] (s.c.)
  给药途径	i.p., s.c.