Tepotinib (EMD 1214063)

Catalog No.S7067

Tepotinib (EMD 1214063) is a potent and selective c-Met inhibitor with IC50 of 4 nM, >200-fold selective for c-Met than IRAK4, TrkA, Axl, IRAK1, and Mer. Phase 1.

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Tepotinib (EMD 1214063) Chemical Structure

Tepotinib (EMD 1214063) Chemical Structure
Molecular Weight: 492.57

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Product Information

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  • Research Area
  • Inhibition Profile

Product Description

Biological Activity

Description Tepotinib (EMD 1214063) is a potent and selective c-Met inhibitor with IC50 of 4 nM, >200-fold selective for c-Met than IRAK4, TrkA, Axl, IRAK1, and Mer. Phase 1.
Targets c-Met [1] IRAK4 [1] TrkA [1] Axl [1]

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IC50 4 nM 615 nM 1.017 μM 1.566 μM
In vitro EMD 1214063 inhibits HGF-induced c-Met phosphorylation in A549 cells with IC50 of 6 nM. Treatment with EMD 1214063 induces a marked reduction of c-Met–constitutive phosphorylation in EBC-1 cells with IC50 of 9 nM. EMD 1214063 effectively blocka phosphorylation of the major downstream effectors of the c-Met enzyme, such as Grb2, Gab1, Sos, PLCγ, and phosphoinositide 3-kinase, in EBC-1, MKN-45, and Hs746T cells in the range of 1 to 10 nM. EMD 1214063 considerably inhibits the viability of MKN-45 cells with IC50 of less than 1 nM. Treatment with EMD 1214063 (as low as 0.1 nM) inhibits HGF-induced NCI-H441 cell migration, whereas concentrations of 100 nM to 1 μM almost completely prevents it. [1]
In vivo EMD 1214063 treatment, at doses of 10 mg/kg or more, results in more than 90% inhibition of c-Met phosphorylation in Hs746T xenograft tumor for a period of at least 72 hours. EMD 1214063 induces more than 50% reduction of cyclin D1 expression, which persists after 96 hours upon treatment with doses of 100 mg/kg. A transient induction of p27 and cleaved caspase-3 are also observed upon treatment with EMD 1214063. EMD 1214063 (15 mg/kg, daily) treatment induces complete regression of gastric carcinoma xenografts Hs746T, in which c-Met is amplified, overexpressed, and activated in a ligand-independent fashion. [1]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

c-Met kinase assay Kinase inhibition by EMD 1214063 (1 and 10μM) is assessed in vitro using a panel of 242 different kinases. Biochemical activity is measured in a flash-plate assay. His6-tagged recombinant human c-Met kinase domain (Aa 974–end; 20 ng) and biotinylated poly-Ala-Glu-Lys-Tyr (6:2:5:1; 500 ng) are incubated with or without the test compound for 90 minutes at room temperature in 100 μL buffer containing 0.3 μCi33P-ATP, 2.5 μg polyethylene glycol 20.000, and 1% dimethyl sulfoxide (DMSO). Radioactivity is measured with a TopCount microplate scintillation and luminescence counter.

Animal Study: [1]

Animal Models Human gastric carcinoma xenografts Hs746T
Formulation
Dosages 15 mg/kg
Administration daily

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] Bladt F, et al. Clin Cancer Res, 2013, 19(11), 2941-2951.

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

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01014936 Completed Patients With Solid Tumors, Either Refractory to Standard Therapy or for Which no Effective Standard Therapy is Available EMD Serono|Merck KGaA November 2009 Phase 1

Chemical Information

Download Tepotinib (EMD 1214063) SDF
Molecular Weight (MW) 492.57
Formula

C29H28N6O2

CAS No. 1100598-32-0
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms MSC2156119
Solubility (25°C) * In vitro DMSO 5 mg/mL warming (10.15 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo
* <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 Benzonitrile, 3-[1,6-dihydro-1-[[3-[5-[(1-methyl-4-piperidinyl)methoxy]-2-pyrimidinyl]phenyl]methyl]-6-oxo-3-pyridazinyl]-

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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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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