Amuvatinib (MP-470) 850879-09-3

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Molecular Weight:

447.51 Amuvatinib (MP-470) is a potent and multi-targeted inhibitor of c-Kit, PDGFRα and Flt3 with IC50 of 10 nM, 40 nM and 81 nM, respectively. Phase 2.


Biological Activity


The hydrochloride salt of MP-470 also inhibits several mutants of c-Kit, including c-KitD816V, c-KitD816H, c-KitV560G, and c-KitV654A, as well as a Flt3 mutant (Flt3D835Y) and two PDGFRα mutants (PDGFRαV561D and PDGFRαD842V),
with IC50 of 10 nM to 8.4 μM. MP-470 potently inhibits the
proliferation of OVCAR-3, A549, NCI-H647, DMS-153, and DMS-114 cells,
with IC50 of 0.9 μM–7.86 μM.


MP-470 also inhibits c-Kit
and PDGFRα, with IC50 values of 31 μM and 27 μM, respectively. MP-470
demonstrates potent cytotoxicity against MiaPaCa-2, PANC-1, and GIST882
cells, with IC50 of 1.6 μM to 3.0 μM. MP-470 also binds to and inhibits
several c-Kit mutants, including c-KitK642E, c-KitD816V, and c-KitK642E/D816V. In MDA-MB-231 cells, MP-470 (1 μM) inhibits tyrosine phosphorylation of AXL.


In LNCaP and PC-3, but not DU145 cells, MP-470 exhibits cytotoxicity
with IC50 of 4 μM and 8 μM, respectively, and induces Apoptosis at 10
μM. In LNCaP cells, MP-470 (10 μM) elicits G1 arrest and decreases
phosphorylation of Akt and ERK1/2. In SF767 cells, MP-470
(10 μM) inhibits c-Met phosphorylation and sensitizes cells to
radiation.


In combination with radiation, MP-470 (10 μM) inhibits
glycogen synthase kinase (GSK)3β activity, induces apoptosis, and
disrupts the repair of dsDNA breaks probably through suppression of
Rad51.


In mice xenograft models of HT-29, A549, and SB-CL2 cells, MP-470 (10
mg/kg–75 mg/kg via i.p. or 50 mg/kg–200 mg/kg via p.o.) inhibits tumor
growth. In mice bearing LNCaP xenograft, MP-470 (20
mg/kg) combined with Erlotinib significantly induces tumor growth
inhibition (TGI).






Kinase inhibition assay of c-Kit and PDGFRα


For the testing of inhibitory activity against c-Kit and PDGFRα, enzymes
are incubated with varying concentrations of MP-470 and radiolabeled γ-32P-ATP.
After 30 min, the reaction mixtures are electrophoresed on an
acrylamide gel and autophosphorylation, quantitated by the amount of
radioactivity incorporated into the enzyme, is assayed.


Method


Cells are plated at a density of 2 × 103 to 1 × 104 cells per well in 100 μL medium on day 0 in 96-well Falcon microtitier
plates. On day 1, ten μL of serial dilutions of MP-470 are added to the
plates in quadruplicates. After incubation for 4 days, the cells are
fixed with 10% Trichloroacetic acid solution. Subsequently, they are
labeled with 0.04% Sulforhodamine B (SRB) in 1% acetic acid.


After
multiple washes to remove the excess dye, 100 μL of 50 mM Tris solution
is added to each well in order to dissolve the dye. The absorbance of
each well is read on a plate reader at 570 nm. Date are expressed as the
percentage of survival of control calculated from the absorbance
corrected for background absorbance.


The surviving percent of cells is
determined by dividing the mean absorbance values of the monoclonal
antibody by mean absorbance values of the control and multiplying by
100.

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Product Categories : Protein Tyrosine Kinase > c-Kit Inhibitor