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MK-2461 c-Met inhibitor

Name: MK-2461
Brand: Selleck Chemicals
SKU: S2774
Rating: 5 (4 reviews)

Cat.No.S2774

MK-2461 is a potent, multi-targeted inhibitor for c-Met(WT/mutants) with IC50 of 0.4-2.5 nM, less potent to Ron, Flt1; 8- to 30-fold greater selectivity of c-Met targets versus FGFR1, FGFR2, FGFR3, PDGFReta, KDR, Flt3, Flt4, TrkA, and TrkB. Phase 1/2.

Chemical Structure

Molecular Weight: 495.55

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Quality Control

Batch: Purity: 99.97%

99.97

Related Targets	EGFR VEGFR PDGFR FGFR Src MEK CSF-1R FLT3 HER2 c-Kit
Other c-Met Inhibitors	Tepotinib Dihexa SGX-523 PHA-665752 Foretinib SU11274 BMS-777607 JNJ-38877605 Tivantinib PF-04217903

Chemical Information, Storage & Stability

Molecular Weight	495.55	Formula	C₂₄H₂₅N₅O₅S	Storage (From the date of receipt)	3 years-20°Cpowder
CAS No.	917879-39-1	Download SDF		Storage of Stock Solutions	1 year-80°Cin solvent 1 month-20°Cin solvent
Synonyms	N/A			Smiles	CN1C=C(C=N1)C2=CC3=C(C=CC4=C(C3=O)C=C(C=C4)NS(=O)(=O)N(C)CC5COCCO5)N=C2

Solubility

In vitro
Batch:

DMSO : 99 mg/mL (199.77 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molarity Calculator

Mass	Concentration	Volume	Molecular Weight
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Dilution Calculator Molecular Weight Calculator

In vivo Batch:
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

In vivo Formulation Calculator (Clear solution)

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% DMSO + % + % Tween 80 + % ddH₂O

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Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )

Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.

Mechanism of Action

Features	Preferentially binds to activated c-Met, distinguished from other known ATP-competitive tyrosine kinase inhibitors (which bind to inactive and active kinases with similar affinity).
Targets/IC₅₀/Ki	c-Met (M1250T) 0.4 nM c-Met (Y1235D) 0.5 nM c-Met (Y1230H) 1.0 nM c-Met (N1100) 1.5 nM c-Met (Y1230C) 1.5 nM c-Met 2.5 nM RON 7 nM FLT1 10 nM FLT3 22 nM PDGFRβ 22 nM Mer 24 nM FGFR2 39 nM KDR 44 nM TrkA 46 nM FGFR3 50 nM TrkB 61 nM FGFR1 65 nM FLT4 78 nM DRAK1 199 nM JAK2 225 nM
In vitro	MK-2461 also potently inhibits FGFR1, FGFR2, FGFR3, KDR, TrkA, TrkB, and Flt4 with IC50 of 65 nM, 39 nM, 50 nM, 44 nM, 46 nM, 61 nM, and 78 nM, respectively. Compared with wild-type c-Met, this compound more potently inhibits the activity of oncogenic c-Met kinase mutants such as N1100Y, Y1230C, Y1230H, Y1235D, and M1250T with IC50 of 1.5 nM, 1.5 nM, 1.0 nM, 0.5 nM, and 0.4 nM, respectively. It binds more strongly to phosphorylated c-Met than to unphosphorylated c-Met. This chemical potently inhibits ATP-induced autophosphorylation of the COOH-terminal docking domain of c-Met, but not the activation loop. In contrast, it inhibits phosphorylation of the activation loop of FGFR2 (Y653/Y654) in Kato III cells and PDGFR (Y849) in H1703 cells with IC50 of <0.3 M. It inhibits HGF-induced mitogenesis of 4MBr-5 cells with IC50 of 204 nM, and HGF-induced migration of HPAF II cells with IC50 of 404 nM, as well as HGF-induced branching tubulogenesis of MDCK cells. In addition, this compound potently inhibits IL-3-independent proliferation of 32D cells transformed with Tpr-Met or Tpr-Met (Y362C) mutant with IC50 of ~100 nM. It significantly inhibits the proliferation of a large panel of tumor cell lines, especially potent against tumor cells harbored genomic amplification of MET or FGFR2.
Kinase Assay	Time-resolved fluorescence resonance energy transfer assay
Kinase Assay	The c-Met–catalyzed phosphorylation of N-biotinylated peptide (EQEDEPEGDYFEWLE-CONH2) is measured using a time-resolved fluorescence resonance energy transfer assay. The IC50 of this compound for Ron, Mer, Flt1, Flt3, Flt4, KDR, PDGFReta, FGFR1, FGFR2, FGFR3, TrkA, and TrkB are determined using time-resolved fluorescence resonance energy transfer assays similar to the c-Met kinase assay.
In vivo	MK-2461 treatment significantly inhibits c-Met (Y1349) phosphorylation in GTL-16 tumours with IC50 of ~1 M. Oral administration of this compound at 10 mg/kg, 50 mg/kg, and 100 mg/kg twice daily as well as 200 mg/kg once daily effectively suppresses tumour growth of GTL-16 xenografts in mice by 62%, 77%, 75%, and 90%, respectively. Similarly, this chemical treatment at 134 mg/kg twice daily inhibits the growth of NIH3T3 tumours harbouring c-Met single nucleotide mutants T3936C and T3997C, by 78% and 62%, respectively.
References	[1] https://pubmed.ncbi.nlm.nih.gov/20145145/ [2] https://pubmed.ncbi.nlm.nih.gov/10094779/

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT00496353	Completed	Neoplasm	Merck Sharp & Dohme LLC	June 2007	Phase 1\|Phase 2
NCT00518739	Completed	Advanced Cancer	Merck Sharp & Dohme LLC	February 2007	Phase 1

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