NPS-1034 is a dual inhibitor of Axl and MET with IC50 values of 10.3 and 48 nM, respectively. NPS-1034 inhibits the viability of the MKN45 and SNU638 cell lines, which highly express the MET gene and p-MET (phosphorylated MET), with IC50 values of 112.7 and 190.3 nmol, respectively. NPS-1034 also inhibits hepatocyte growth factor (HGF)-stimulated MET autophosphorylation (Y1234/1235) in the AGS and MKN1 cell lines with IC50 values of <10 and <50 nmol, respectively.
In vivo, NPS-1034 (10 mg/kg, p.o.) decreases tumor growth in SCID mice bearing HCC827/GR tumor xenografts. In nude mice bearing MKN45 xenograft tumors, NPS-1034 (30 mg/kg, p.o.) decreases tumor growth through the inhibition of angiogenesis and the promotion of apoptosis.
|Cell lines||HCC827/GR, HCC-78 and H820 cells|
|Preparation method||To perform the MTT assay, cells (0.5 × 104/well) are plated in 96-well sterile plastic plates and allowed to attach overnight. Cells are exposed to varying doses of gefitinib, erlotinib, PHA-665752, and NPS-1034 in medium containing 1% FBS. After 72 hours, 15 μL of MTT solution (5 mg/mL) is added to each well and plates are incubated for 4 hours. Crystalline formazan is solubilized with 100 μL of a 10% (w/v) SDS solution for 24 hours. Absorbance at 595 nm is read spectrophotometrically using a microplate reader.|
|Incubation time||72 h|
|Animal models||SCID mice bearing HCC827/GR tumor xenografts|
|Dosages||10 mg/kg, 5 days a week|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||DMSO: ≥ 40 mg/mL warmed|
|Related c-Met Products|
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Glumetinib, also known as SCC244, is a novel, potent and highly selective inhibitor of c-Met with an IC50 of 0.42 nM.
CEP-40783 (RXDX-106) is a potent, selective and orally available inhibitor of AXL and c-Met with IC50 values of 7 nM and 12 nM, respectively.
Savolitinib (volitinib, AZD6094, HMPL-504) is a novel, potent, and selective MET inhibitor currently in clinical development in various indications, including PRCC. The IC50 values of this compound for c-Met and p-Met are 5 nM and 3 nM, respectively. It shows exquisite selectivity for c-Met over 274 kinase.
AMG 337 is an oral, small molecule, ATP-competitive, highly selective inhibitor of the MET receptor.
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