NPS-1034

NPS-1034 - Names and Identifiers

Name	N-(3-fluoro-4-((3-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide.
Synonyms	NPS-1034 2-(4-Fluorophenyl)-N-[3-fluoro-4-[(3-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]-2,3-dihydro-1,5-dimethyl-3-oxo-1H-pyrazole-4-carboxamide N-(3-fluoro-4-((3-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenyl)-2-(4-fluorophenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamide. 1H-Pyrazole-4-carboxamide, 2-(4-fluorophenyl)-N-[3-fluoro-4-[(3-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]-2,3-dihydro-1,5-dimethyl-3-oxo-
CAS	1221713-92-3

NPS-1034 - Physico-chemical Properties

Molecular Formula	C31H23F2N5O3
Molar Mass	551.54
Density	1.416±0.06 g/cm3(Predicted)
Solubility	Soluble in DMSO, not in water
pKa	11.05±0.70(Predicted)
Storage Condition	-20℃
Use	NPS-1034 is a novel MET inhibitor, which inhibits the activated MET receptor and its constitutively active mutants. 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. Notably, NPS-1034 inhibited three MET variants that are resistant to the MET inhibitors SU11274, NVP-BVU972, and PHA665752.
In vitro study	In HCC827/GR cells, NPS-1034 did not exhibit a significant anti-proliferative effect and was able to overcome gefitinib resistance by inhibiting phosphorylation of MET,Akt, and Erk. In H820 cells, NPS-1034 increased sensitivity to EGFR-TKIs. In HCC78 cells, ROS1 activity and cell proliferation were inhibited by NPS-1034. In addition, binding of gefitinib and NPS-1034 enhanced cell death by inducing caspase-3 and PARP-1 lysis. NPS-1034 inhibited the activity of MKN45 and SNU638 cell lines highly expressing MET gene and p-MET, with IC50 of 112.7 and 190.3 nmol, respectively.
In vivo study	In SCID mice loaded with HCC827/GR tumor xenografts, NPS-1034 (10 mg/kg, p.o.) reduces tumor growth, and in combination with gefitinib and NPS-1034 enhances tumor growth inhibition by inhibiting tumor proliferation and inducing apoptosis. NPS-1034 (30 mg/kg, p.o.) reduced tumor growth by inhibiting angiogenesis and promoting apoptosis in nude mice bearing MKN45 xenografts.

NPS-1034 - Reference

Reference

1. Rho JK, et al. MET and AXL inhibitor NPS-1034 exerts efficacy against lung cancer cells resistant to EGFR kinase inhibitors because of MET or AXL activation. Cancer Res. 2014 Jan 1;74(1):253-62.2. Shin JS, et al. NPS-1034, a novel MET inhibitor, inhibits the activated MET receptor and its constitutively active mutants. Invest New Drugs. 2014 Jun;32(3):389-99.