Masitinib (AB1010)

Catalog No.S1064

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.

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Masitinib (AB1010) Chemical Structure

Masitinib (AB1010) Chemical Structure
Molecular Weight: 498.64

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Product Information

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  • Research Area
  • Inhibition Profile

Product Description

Biological Activity

Description 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.
Targets Kit [1] Lyn B [1] PDGFRα [1] PDGFRβ [1]

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IC50 200 nM 510 nM 540 nM 800 nM
In vitro Masitinib is a competitive inhibitor against ATP at concentrations ≤500 nM. Masitinib also potently inhibits recombinant PDGFR and the intracellular kinase Lyn, and to a lesser extent, fibroblast growth factor receptor 3. In contrast, Masitinib demonstrates weak inhibition of Abl and c-Fms. Masitinib more strongly inhibits degranulation, cytokine production, and bone marrow mast cell migration than imatinib. In Ba/F3 cells expressing human wild-type Kit, Masitinib inhibits SCF (stem cell factor)-induced cell proliferation with an IC50 of 150 nM, while the IC50 for inhibition of IL-3-stimulated proliferation is at approximately >10 µM. In Ba/F3 cells expressing PDGFRα, Masitinib inhibits PDGF-BB-stimulated proliferation and PDGFRα tyrosine phosphorylation with IC50 of 300 nM. Masitinib also causes inhibition of SCF-stimulated tyrosine phosphorylation of human Kit in mastocytoma cell-lines and BMMC. Masitinib inhibits Kit gain-of-function mutants, including V559D mutant and Δ27 mouse mutant with IC50 of 3 and 5 nM in Ba/F3 cells. Masitinib inhibits the cell proliferation of mastocytoma cell lines including HMC-1α155 and FMA3 with IC50 of 10 and 30 nM, respectively. [1] Masitinib inhibits cell growth and PDGFR phosphorylation in two novel ISS cell lines, which suggest that Masitinib displays activity against both primary and metastatic ISS cell line and may aid in the clinical management of ISS. [2]
In vivo Masitinib inhibits tumour growth and increases the median survival time in Δ27-expressing Ba/F3 tumor models at 30 mg/kg, without cardiotoxicity or genotoxicity. [1] Masitinib (12.5 mg/kg/d PO) increases overall TTP (time-to-tumor progression) compared with placebo in dogs. [3] The combination of masitinib/gemcitabine shows synergy in vitro on proliferation of gemcitabine-refractory cell lines Mia Paca2 and Panc1, and to a lesser extent on Mia Paca-2 pancreatic tumours in Nog璖CID mice. [4]
Features Potential low side-effect profile.

Protocol(Only for Reference)

Kinase Assay: [1]

In vitro enzyme-linked immunoassay with recombinant protein kinases A 96-well microtitre plateis coated overnight with 0.25 mg/ml poly(Glu,Tyr 4:1), rinsed twice with 250 µL of washing buffer (10 mM phosphate-buffered saline [pH 7.4] and 0.05% Tween 20) and dried for 2 hours at room temperature. Assays are performed at room temperature with a final volume of 50 µL in kinase buffer (10 mM MgCl2, 1 mM MnCl2, 1 mM sodium orthovanadate, 20 mM HEPES, pH 7.8) containing ATP at a concentration of at least twice the Km for each enzyme and an appropriate amount of recombinant enzyme to ensure a linear reaction rate. Reactions are initiated upon introduction of the enzyme and terminated with the addition of one reaction volume (50 μL) of 100 mM EDTA per 5 M urea mix. Plates are washed three times and incubated with 1:30,000 horseradish peroxidase-conjugated anti-phosphotyrosine monoclonal antibody, then washed three times and incubated with tetramethylbenzidine. The final reaction product is quantified by spectrophotometry at 450 nm.

Cell Assay: [1]

Cell lines Ba/F3 cells expressing wild-type or mutant human Kit, HMC1, HMC-1α155
Concentrations 0.1 nM - 10 μM
Incubation Time 48 hours
Method For the assay of Ba/F3 cell proliferation, microtitre plates are seeded with a total of 104 cells/well in 100 μL of RPMI 1640 medium with 10% foetal bovine serum at 37 °C. These are supplemented, or not, with either 0.1% conditioned medium from X63-IL-3 cells or 250 ng/mL murine SCF. The murine SCF, which activates Kit, is purified from the conditioned medium of SCF-producing CHO cells. Cells are grown for 48 hours at 37 °C with Masitinib and then incubated with 10 μL/well of WST-1 reagent for 3 hours at 37 °C. The amount of formazan dye formed is quantified by its absorbance at 450 nm using a scanning multiwell spectrophotometer. A blank well without cells is used as a background control for the spectrophotometer.

Animal Study: [1]

Animal Models Ba/F3 Δ27 tumour model in female MBRI Nu/Nu mice
Formulation DMSO
Dosages 30 mg/kg (intraperitoneal) or 10, 30, or 45 mg/kg (orally).
Administration Intraperitoneal or orally administered.

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

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
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] Dubreuil P, et al. PLoS One, 2009, 4(9), e7258.

[2] Lawrence J, et al. Vet Comp Oncol, 2011, doi: 10.1111/j.1476-5829.2011.00291.x.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02490488 Active, not recruiting Ovarian Cancer AB Science April 2014 Phase 2
NCT02605044 Recruiting 2nd Line Metastatic Colorectal Cancer AB Science January 2014 Phase 3
NCT02009423 Not yet recruiting Gastro-Intestinal Stromal Tumour AB Science January 2014 Phase 3
NCT02588677 Active, not recruiting Amyotrophic Lateral Sclerosis (ALS) AB Science April 2013 Phase 2|Phase 3
NCT01694277 Recruiting Gastrointestinal Stromal Tumors AB Science April 2012 Phase 3

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Chemical Information

Download Masitinib (AB1010) SDF
Molecular Weight (MW) 498.64
Formula

C28H30N6OS

CAS No. 790299-79-5
Storage 3 years -20℃powder
2 years -80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 100 mg/mL (200.54 mM)
Ethanol 4 mg/mL (8.02 mM)
Water <1 mg/mL
In vivo 4% DMSO+30% PEG 300+5% Tween 80+ddH2O 30mg/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.
Chemical Name N-(4-methyl-3-(4-(pyridin-3-yl)thiazol-2-ylamino)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide

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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