Amuvatinib (MP-470)

Catalog No.S1244
4.5 5 4 Product Citations

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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Amuvatinib (MP-470) Chemical Structure

Amuvatinib (MP-470) Chemical Structure
Molecular Weight: 447.51

Validation & Quality Control

Customer Reviews(1)

Quality Control & MSDS

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Product Information

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  • Research Area

Product Description

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]
IC50 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]
Features

Protocol(Only for Reference)

Kinase Assay: [2]

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 Assay: [2]

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.

Animal Study: [1]

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)
Solubility 30% PEG400/0.5% Tween80/5% propylene glycol, 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.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Bearss DJ, et al. US Patent, US/2008/0226747.

[2] Hurley LH, et al. World Patent, WO/2005/037825.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-10-24)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01357395 Active, not recruiting Small Cell Lung Carcinoma Astex Pharmaceuticals May 2011 Phase 2
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 --

Chemical Information

Download Amuvatinib (MP-470) SDF
Molecular Weight (MW) 447.51
Formula

C23H21N5O3S

CAS No. 850879-09-3
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms HPK 56
Solubility (25°C) * In vitro DMSO 32 mg/mL (71 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 30% PEG400/0.5% Tween80/5% propylene glycol 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* 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.

Research Area

Customer Reviews (1)


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Rating
Source Dr. Yong-Weon Yi from Georgetown University Medical Center. Amuvatinib (MP-470) purchased from Selleck
Method MTT assays
Cell Lines UWB1.289 cells, A2780Cis cells
Concentrations 0-10 μM
Incubation Time 72 h
Results MP-470 treatments reduced UWB1.289 cells and A2780Cis cells growth in a dose-dependent manner.

Product Citations (4)

Tech Support & FAQs

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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