生物活性

• 靶点

  Axl IC50:10.3nM

  c-Met IC50:48nM

• 描述MET amplification contributes to the acquisition of resistance to EGFRTKIs because it is a redundant pathway for the activation of PI3K/Akt signaling. AXl belongs to the TAM (Tyro-Axl-Mer) receptor tyrosine kinase (RTK) family and is characterized by 2 immunoglobulin like domains, dual fibronectin type II repeats in the extracellular domain. NPS-1034 is a dual Met/Axl inhibitor with IC50 of 48 nM and 10.3 nM respectively. In HCC827/GR cells, single treatment of NPS-1034 have showed no significant antiproliferative effects, while combined with gefitinib could overcome resistance of gefitinib by inhibiting the phosphorylation of MET, Akt, and Erk. Also in HCC78 cells, cell proliferation was inhibited by NPS-1034 and the degree of growth inhibition was similar to that produced by crizotinib suggesting ROS1 activity and cell proliferation were inhibited. In addition, a combination of gefitinib and NPS-1034 enhances cell death by inducing caspase-3 and PARP-1 cleavage. In SCID mice bearing HCC827/GR tumor xenografts, NPS-1034 (10 mg/kg) decreases tumor growth, and the combination of gefitinib and NPS-1034 results in enhanced tumor growth inhibition via the inhibition of tumor proliferation and apoptosis. NPS-1034 showed significant inhibitory activity against AXL, CSF1R, DDR, FLT3, KIT, MERTK, MET, MST1R, ROS, TIE1, and TRK in an assay that used 1 μmol/L ATP. In gastric cancer cell lines AGS, KATOIII, NCI-N87, MKN1, MKN28, MKN45, MKN74, and SNU638 cells, NPS-1034 inhibited them with IC50 of 4 nmol/L. Furthermore, the viability of the MKN45 and SNU638 cell lines were inhibited by NPS-1034with IC50 values of 112.7 and 190.3 nmol, respectively. In contrast, NPS-1034 inhibited AGS, KATOIII, NCI-N87, MKN1, MKN28, and MKN74 cell viability with IC50 values ranging from 1 μmol to more than 10 μmol. NPS-1034 inhibited HGF-stimulated MET autophosphorylation (Y1234/1235) in the AGS and MKN1 cell lines with IC50 values of <10 and <50 nmol, respectively. NPS-1034 also blocked the phosphorylation of the MET downstream signaling molecules, AKT and ERK. Additionally, NPS-1034-treated mice showed virtually no weight loss, indicating that NPS-1034 is generally well tolerated.

• 动物研究
  剂量	SCID Mice: 10 mg/kg[1] (p.o.) Balb/C nude Mice: 30 mg/kg[2] (p.o.) Mice: 50 mg/kg[3] (p.o.)
  给药途径	p.o.