Amuvatinib (MP-470)

Catalog No.S1244 Synonyms: HPK 56

Amuvatinib (MP-470) Chemical Structure

Molecular Weight(MW): 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.

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In DMSO USD 235 In stock
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Cited by 6 Publications

4 Customer Reviews

  • Effects of treatment for 48h with a vehicle or the indicated doses of MP-470 in parental or ER1 and ER2 cell lines in the absence and presence of erlotinib on the indicated biomarkers. Data represent 3 independent experiments.

    Nat Genet 2012 44(8), 852-60. Amuvatinib (MP-470) purchased from Selleck.

    Inactivation of AXL by MP470 reverses epithelial to mesenchymal transition. Immunoblot analyses of lysates from TGFβ/TNFα- treated MCF10A cells treated with varying amounts of MP470 for 72 hours.

    Oncogene 2014 33(10), 1316-24. Amuvatinib (MP-470) purchased from Selleck.

  • Amuvatinib (3 umol/l, 72 h) leads to decreased pAXL, pAKT, and pERK expression by western blot.

    Melanoma Res 2014 24(5), 448-53. Amuvatinib (MP-470) purchased from Selleck.

    For MTT assays, cells (2,000 ~ 5,000 cells/well) were subcultured into 96-well plates according to their growth properties. Cell proliferation was assayed at 72 hr after treatment of MP-470 by adding 20 μl of 5 mg/ml 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) solution per 100 μl of growth medium. After incubating for 3-4 h at 37°C, the media were removed and 150 µl/well of MTT solvent (either absolute DMSO or isopropanol containing 4 mM HCl and 0.1% Nonidet-40) was added to dissolve the formazan.

    Dr. Yong-Weon Yi from Georgetown University Medical Center. Amuvatinib (MP-470) purchased from Selleck.

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Choose Selective c-Kit Inhibitors

Biological Activity

Description 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.
Targets
c-Kit (D816H) [1] PDGFRα (V561D) [1] FLT3 (D835Y) [1]
10 nM 40 nM 81 nM
In vitro

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. [1] 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. [2] In MDA-MB-231 cells, MP-470 (1 μM) inhibits tyrosine phosphorylation of AXL. [3] 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. [4] 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. [5] [6]

In vivo 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. [1] In mice bearing LNCaP xenograft, MP-470 (20 mg/kg) combined with Erlotinib significantly induces tumor growth inhibition (TGI). [4]

Protocol

Kinase Assay:[2]
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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.
Cell Research:[2]
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  • Cell lines: MiaPaCa-2, PANC-1, and GIST882 cells
  • Concentrations: 0–30 μM, dissolved in DMSO
  • Incubation Time: 96 hours
  • 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.
    (Only for Reference)
Animal Research:[1]
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  • Animal Models: Mice (athymic nude) xenograft models of HT-29, A549, and SB-CL2 cells
  • Formulation: Dissolved in corn oil for p.o.; Dissolved in TV-10 (60% propylene glycol, 30% PEG300, 10% water, and 150 mg/mL 2-hydroxypropyl-β-cyclodextrin) or TV-10 (5% ethanol, 40% glycerol, 55% water, and 300 mg/mL cyclodextrin) for i.p.
  • Dosages: 10 mg/kg–75 mg/kg (i.p.) or 50 mg/kg–200 mg/kg (p.o.)
  • Administration: Oral gavage (qd5 × 3 weeks) or intraperitoneal injection (qd5 × 2 weeks)
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 32 mg/mL (71.5 mM)
Water Insoluble
Ethanol Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
30% PEG400+0.5% Tween80+5% propylene glycol
For best results, use promptly after mixing. 		30 mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 447.51
Formula

C23H21N5O3S
CAS No. 850879-09-3
Storage powder
in solvent
Synonyms HPK 56

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01357395 Completed Small Cell Lung Carcinoma Astex Pharmaceuticals May 2011 Phase 2
NCT01357395 Completed Small Cell Lung Carcinoma Astex Pharmaceuticals May 2011 Phase 2
NCT00881166 Completed Malignant Disease Astex Pharmaceuticals November 2007 Phase 1
NCT00881166 Completed Malignant Disease Astex Pharmaceuticals November 2007 Phase 1
NCT00894894 Completed Solid Tumors Astex Pharmaceuticals May 2007 Phase 1
NCT00504205 Terminated Lymphoma|Unspecified Adult Solid Tumor Protocol Specific Astex Pharmaceuticals|National Cancer Institute (NCI) May 2007 Not Applicable

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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c-Kit Signaling Pathway Map

c-Kit Inhibitors with Unique Features

  • Most Potent Kit Inhibitor

    Axitinib : c-Kit, IC50=1.7 nM.

  • FDA-approved Kit Inhibitor

    Imatinib Mesylate (STI571) : Approved by FDA for CML, GISTs and a number of other malignancies.

  • Newest Kit Inhibitor

    Tyrphostin AG 1296 : An inhibitor of PDGFR with IC50 of 0.3-0.5 μM, inhibiting FGFR and c-Kit with IC50 of 12.3 μM and 1.8 μM in Swiss 3T3 cells.

  • Classic Kit Inhibitor

    Dovitinib (TKI-258, CHIR-258) : Multitargeted RTK inhibitor for class III (FLT3/c-Kit), class IV (FGFR1/3) and class V (VEGFR1-4) RTKs.

Related c-Kit Products4

  • Erlotinib New

    Erlotinib is an EGFR inhibitor with IC50 of 2 nM, >1000-fold more sensitive for EGFR than human c-Src or v-Abl.

  • R428 (BGB324) New

    R428 (BGB324) is an inhibitor of Axl with IC50 of 14 nM, >100-fold selective for Axl versus Abl. Selectivty for Axl is also greater than Mer and Tyro3 (50-to-100- fold more selective) and InsR, EGFR, HER2, and PDGFRβ (100- fold more selective).

  • Pexidartinib (PLX3397) New

    Pexidartinib (PLX3397) is an oral, potent mutil-targeted receptor tyrosine kinase inhibitor of CSF-1R, Kit, and Flt3 with IC50 of 20 nM, 10 nM and 160 nM, respectively. Phase 3.

  • Masitinib (AB1010)

    Masitinib is a novel inhibitor for Kit and PDGFRα/β with IC50 of 200 nM and 540 nM/800 nM, weak inhibition to ABL and c-Fms. Phase 3.

    Features:Potential low side-effect profile.

  • OSI-930

    OSI-930 is a potent inhibitor of Kit, KDR and CSF-1R with IC50 of 80 nM, 9 nM and 15 nM, respectively; also potent to Flt-1, c-Raf and Lck and low activity against PDGFRα/β, Flt-3 and Abl. Phase 1.

  • Gefitinib (ZD1839)

    Gefitinib (ZD-1839) is an EGFR inhibitor for Tyr1173, Tyr992, Tyr1173 and Tyr992 in the NR6wtEGFR and NR6W cells with IC50 of 37 nM, 37nM, 26 nM and 57 nM, respectively.

    Features:A potent EGFR tyrosine kinase inhibitor.

  • Erlotinib HCl (OSI-744)

    Erlotinib HCl (OSI-744) is an EGFR inhibitor with IC50 of 2 nM in cell-free assays, >1000-fold more sensitive for EGFR than human c-Src or v-Abl.

  • Crizotinib (PF-02341066)

    Crizotinib (PF-02341066) is a potent inhibitor of c-Met and ALK with IC50 of 11 nM and 24 nM in cell-based assays, respectively.

  • Afatinib (BIBW2992)

    Afatinib (BIBW2992) inhibits EGFR/ErbB irreversibly in vitro with IC50 of 0.5, 0.4, 10, 14, 1 nM for EGFRwt, EGFR L858R , EGFR L858R/T790M ErbB2 (HER2) and ErbB4 (HER4), respectively.

  • Osimertinib (AZD9291)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID