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Purity: ≥98%
NPS-1034 (NPS1034; NPS 1034) is a novel, potent dual inhibitor of the tyrosine kinases Met and Axl with potential antineoplastic activity. With IC50s of 48 nM and 10.3 nM, respectively, it inhibits Met and Axl. By encouraging the regression of tumors in a mouse xenograft through anti-angiogenic and pro-apoptotic actions, NPS-1034 exhibits strong anti-proliferative activity in vitro against cells expressing MET and high in vivo antitumor efficacy.
| Targets |
AXL (IC50 = 10.3 nM); MET (IC50 = 48 nM)
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| ln Vitro |
NPS-1034 overcomes gefitinib resistance in HCC827/GR cells by blocking the phosphorylation of MET, Akt, and Erk, but it has no discernible antiproliferative effects. NPS-1034 increases H820 cells' susceptibility to EGFR-TKIs. NPS-1034 inhibits ROS1 activity and cell proliferation in HCC78 cells. Furthermore, by causing caspase-3 and PARP-1 cleavage, the combination of gefitinib and NPS-1034 increases cell death.[1] With an IC50 of 112.7 and 190.3 nmol, respectively, NPS-1034 suppresses the MET gene and p-MET, which are highly expressed in the MKN45 and SNU638 cell lines.[2]
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| ln Vivo |
NPS-1034 (10 mg/kg, p.o.) reduces tumor growth in SCID mice harboring HCC827/GR tumor xenografts, and the combination of NPS-1034 and gefitinib leads to increased tumor growth inhibition through the suppression of tumor proliferation and the induction of apoptosis.[1] NPS-1034 (30 mg/kg, p.o.) reduces tumor growth in nude mice with MKN45 xenograft tumors by inhibiting angiogenesis and promoting apoptosis.[2]
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| Enzyme Assay |
RTK assay kits are used in accordance with the manufacturer's protocols to analyze the in vitro NPS-1034 profile of inhibition of RTKs.
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| Cell Assay |
In order to carry out the MTT assay, 0.5 × 104 cells per well are plated in 96-well sterile plastic plates and left to attach for the entire night. In a medium with 1% FBS, cells are exposed to different doses of PHA-665752, NPS-1034, erlotinib, and gefitinib. Following a 72-hour period, each well receives 15 μL of MTT solution (5 mg/mL), and the plates are incubated for a further 4 hours. For 24 hours, 100 μL of a 10% (w/v) SDS solution is used to solubilize crystalline formazan. Using a microplate reader, the absorbance at 595 nm is measured spectrophotometrically.
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| Animal Protocol |
The mice used are female, 6-week-old, 17–20 g severe combined immunodeficiency (SCID) mice. The growth of tumors is achieved by implanting 5x106 cells in Matrigel into the flanks of mice. Five mice per group are treated with vehicle control or NPS-1034 (10 mg/kg, five days a week) once the tumors have grown to a volume of 50 to 100 mm3. NPS-1034 is taken orally. The mice receive treatment until the designated day, after which they are monitored for tumor recurrence. Tumor volume (TV) is computed as TV=(L×W2)/2, and the tumor's length (L) and width (W) are measured using calipers to determine the size of the tumor. As directed by the suppliers, immunohistochemical staining is carried out using a particular primary antibody, the EnVision Plus staining kit, and the APO-Direct terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay kit. Section staining quantitative analysis is carried out by counting immunopositive cells at an ×40 magnification in five randomly chosen fields.
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| References |
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| Molecular Formula |
C31H23F2N5O3
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| Molecular Weight |
551.54
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| Exact Mass |
551.176
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| Elemental Analysis |
C, 67.51; H, 4.20; F, 6.89; N, 12.70; O, 8.70
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| CAS # |
1221713-92-3
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| Related CAS # |
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| PubChem CID |
46194178
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| Appearance |
white solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.695
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| LogP |
5.61
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
41
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| Complexity |
998
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1C([H])=C(C([H])=C([H])C=1OC1C([H])=C([H])N=C2C=1C(=C([H])N2[H])C1C([H])=C([H])C([H])=C([H])C=1[H])N([H])C(C1C(N(C2C([H])=C([H])C(=C([H])C=2[H])F)N(C([H])([H])[H])C=1C([H])([H])[H])=O)=O
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| InChi Key |
RGAZVGZUBCFHRJ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C31H23F2N5O3/c1-18-27(31(40)38(37(18)2)22-11-8-20(32)9-12-22)30(39)36-21-10-13-25(24(33)16-21)41-26-14-15-34-29-28(26)23(17-35-29)19-6-4-3-5-7-19/h3-17H,1-2H3,(H,34,35)(H,36,39)
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| Chemical Name |
1-(4-fluorophenyl)-N-[3-fluoro-4-[(3-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl]-2,3-dimethyl-5-oxopyrazole-4-carboxamide
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| Synonyms |
NPS-1034; NPS 1034; NPS1034
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8131 mL | 9.0655 mL | 18.1311 mL | |
| 5 mM | 0.3626 mL | 1.8131 mL | 3.6262 mL | |
| 10 mM | 0.1813 mL | 0.9066 mL | 1.8131 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Effects of combined treatment with gefitinib and NPS-1034 in HCC827/GR cells with MET gene amplification. Cancer Res. 2014 Jan 1;74(1):253-62. |
Effects of combined treatment with erlotinib and NPS-1034 in HCC827/ER cells with AXL activation. Cancer Res. 2014 Jan 1;74(1):253-62. |
NPS-1034 treatment inhibited ROS1 activity. A, HCC-78 cells treated with the indicated doses of crizotinib or NPS-1034 for 72 hours. The viability of cells was determined using the MTT assay. B, cells treated with or without the indicated doses of crizotinib or NPS-1034 for 24 hours. Changes in ROS, Akt, and Erk activity and cleaved PARP were analyzed by Western blotting. Cancer Res. 2014 Jan 1;74(1):253-62. |
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