NPS-1034

NPS-1034 is a MET inhibitor with IC50 of 4 nmol/L [1].

The hepatocyte growth factor receptor tyrosine kinase MET is required for various morphogenetic events and controls the malignant progression of many human tumors. In various advanced human cancer, gene amplification can deregulate MET [1].

In MKN45 and SNU638 cell lines highly expressing the MET gene and p-MET (phosphorylated MET), IC50 values of NPS-1034 to inhibit cell viability were 112.7 and 190.3 nmol, respectively. In AGS, KATOIII, NCI-N87, MKN1, MKN28, and MKN74 cells, the IC50 values of NPS-1034 to inhibit cell viability ranged from 1 μmol to more than 10 μmol. In MKN45 cells, treatment with NPS-1034 dramatically decreased MET phosphorylation (activation). But in MKN28 cells, MET phosphorylation was not dramatically decreased. This meant that the anti-proliferative effect of NPS-1034 was resulted from its inhibition of p-MET [1].

In nude mice bearing MKN45 tumors, after the diameter of MKN45 tumors had reached about 180 mm3, NPS-1034 at a dose of 30 mg/kg or PBS as vehicle was orally administered once daily for 25 days. It was found that NPS-1034 inhibited the proliferation of tumors highly expressing p-MET. Without drug treatment, neovascularization appeared in tumors in nude mice when the tumor volume was >150 mm3. NPS-1034 treatment clearly decreased the vascularization of the tumors in nude mice [1].

Reference:
[1].  Shin JS, Hong SW, Moon JH, et al. NPS-1034, a novel MET inhibitor, inhibits the activated MET receptor and its constitutively active mutants. Investigational new drugs, 2014, 32(3): 389-399.

MET and AXL inhibitor NPS-1034 exerts efficacy against lung cancer cells resistant to EGFR kinase inhibitors because of MET or AXL activation.[Pubmed:24165158]

Cancer Res. 2014 Jan 1;74(1):253-62.

In non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, acquired resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKI) can occur through a generation of bypass signals such as MET or AXL activation. In this study, we investigated the antitumor activity of NPS-1034, a newly developed drug that targets both MET and AXL, in NSCLC cells with acquired resistance to gefitinib or erlotinib (HCC827/GR and HCC827/ER, respectively). Characterization of H820 cells and evaluation of NPS-1034 efficacy in these cells were also performed. The resistance of HCC827/GR was mediated by MET activation, whereas AXL activation led to resistance in HCC827/ER. The combination of gefitinib or erlotinib with NPS-1034 synergistically inhibited cell proliferation and induced cell death in both resistant cell lines. Accordingly, suppression of Akt was noted only in the presence of treatment with both drugs. NPS-1034 was also effective in xenograft mouse models of HCC827/GR. Although the H820 cell line was reported previously to have T790M and MET amplification, we discovered that AXL was also activated in this cell line. There were no antitumor effects of siRNA or inhibitors specific for EGFR or MET, whereas combined treatment with AXL siRNA or NPS-1034 and EGFR-TKIs controlled H820 cells, suggesting that AXL is the main signal responsible for resistance. In addition, NPS-1034 inhibited cell proliferation as well as ROS1 activity in HCC78 cells with ROS1 rearrangement. Our results establish the efficacy of NPS-1034 in NSCLC cells rendered resistant to EGFR-TKIs because of MET or AXL activation or ROS1 rearrangement.

NPS-1034, a novel MET inhibitor, inhibits the activated MET receptor and its constitutively active mutants.[Pubmed:24173966]

Invest New Drugs. 2014 Jun;32(3):389-99.

The MET proto-oncogene product, which is the receptor for hepatocyte growth factor (HGF), has been implicated in tumorigenesis and metastatic progression. Point mutations in MET lead to the aberrant activation of the receptor in many types of human malignancies, and the deregulated activity of MET has been correlated with tumor growth, invasion, and metastasis. MET has therefore attracted considerable attention as a potential target in anticancer therapy. Here, we report that a novel MET kinase inhibitor, NPS-1034, inhibits various constitutively active mutant forms of MET as well as HGF-activated wild-type MET. NPS-1034 inhibited the proliferation of cells expressing activated MET and promoted the regression of tumors formed from such cells in a mouse xenograft model through anti-angiogenic and pro-apoptotic actions. NPS-1034 also inhibited HGF-stimulated activation of MET signaling in the presence or absence of serum. Furthermore, when tested on 27 different MET variants, NPS-1034 inhibited 15 of the 17 MET variants that exhibited autophosphorylation with nanomolar potency; only the F1218I and M1149T variants were not inhibited by NPS-1034. Notably, NPS-1034 inhibited three MET variants that are resistant to the MET inhibitors SU11274, NVP-BVU972, and PHA665752. Together, these results suggest that NPS-1034 can be used as a potent therapeutic agent for human malignancies bearing MET point mutations or expressing activated MET.