MK-2461

貨號 Cat. No.: S2774
規格 Size: 5~200mg
品牌 Brand: Selleckchem

Description

MK-2461

Catalog 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, PDGFRβ, KDR, Flt3, Flt4, TrkA, and TrkB. Phase 1/2. .

Size

Price

Stock

Quantity

10mM/1mLIn DMSO	USD 680	In stock	0 1 2 3 4 5 6 7 8 9 10
5mg	USD 340	In stock	0 1 2 3 4 5 6 7 8 9 10
10mg	USD 592	In stock	0 1 2 3 4 5 6 7 8 9 10
50mg	USD 2104	In stock	0 1 2 3 4 5 6 7 8 9 10
100mg	USD 3112	In stock	0 1 2 3 4 5 6 7 8 9 10

Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw

Biological Activity

Description	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, PDGFRβ, KDR, Flt3, Flt4, TrkA, and TrkB. Phase 1/2. .
Targets	c-Met	Ron	Flt1/3	PDGFRβ	Mer	FGFR1/2/3
IC50	2.5 nM	7 nM	10 nM/22 nM	22 nM	24 nM	65 nM/39 nM/50 nM ^[1]
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, MK-2461 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. MK-2461 binds more strongly to phosphorylated c-Met than to unphosphorylated c-Met. MK-2461 potently inhibits ATP-induced autophosphorylation of the COOH-terminal docking domain of c-Met, but not the activation loop. In contrast, MK-2461 inhibits phosphorylation of the activation loop of FGFR2 (Y653/Y654) in Kato III cells and PDGFRα (Y849) in H1703 cells with IC50 of <0.3 μM. MK-2461 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, MK-2461 potently inhibits IL-3-independent proliferation of 32D cells transformed with Tpr-Met or Tpr-Met (Y362C) mutant with IC50 of ~100 nM. MK-2461 significantly inhibits the proliferation of a large panel of tumor cell lines, especially potent against tumor cells harbored genomic amplification of MET or FGFR2. ^[1]
In vivo	MK-2461 treatment significantly inhibits c-Met (Y1349) phosphorylation in GTL-16 tumors with IC50 of ~1 μM. Oral administration of MK-2461 at 10 mg/kg, 50 mg/kg, and 100 mg/kg twice daily as well as 200 mg/kg once daily effectively suppresses tumor growth of GTL-16 xenografts in mice by 62%, 77%, 75%, and 90%, respectively. Similarly, MK-2461 treatment at 134 mg/kg twice daily inhibits the growth of NIH3T3 tumors harboring c-Met single nucleotide mutants T3936C and T3997C, by 78% and 62%, respectively. ^[1]
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).

Protocol(Only for Reference)

Kinase Assay: ^[1]

Time-resolved fluorescence resonance energy transfer assay	The c-Met–catalyzed phosphorylation of N-biotinylated peptide (EQEDEPEGDYFEWLE-CONH2) is measured using a time-resolved fluorescence resonance energy transfer assay. ^[2] The MK-2461 IC50 for Ron, Mer, Flt1, Flt3, Flt4, KDR, PDGFRβ, FGFR1, FGFR2, FGFR3, TrkA, and TrkB are determined using time-resolved fluorescence resonance energy transfer assays similar to the c-Met kinase assay.

Cell Assay: ^[1]

Cell lines	SW480, HT29, SW620, Colo 205, HCT116, HCT15, Colo 201, SCC-9, H1993, H1048, GTL-16, SNU15, et al.
Concentrations	Dissolved in DMSO, final concentrations ~100 μM
Incubation Time	72 hours
Method	Cells are exposed to various concentrations of MK-2461 for 72 hours. The viability of tumor cells is measured using the ViaLight PLUS kit.

Animal Study: ^[1]

Animal Models	Female nude CD-1 nu/nu mice inoculated s.c. with GTL-16 cells or c-Met mutant-transformed NIH3T3 cells
Dosages	~134 mg/kg
Administration	Orally once or twice daily
Solubility	1% DMSO/30% polyethylene glycol/1% Tween 80, pH 4 15 mg/mL

References

Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number	Recruitment	Conditions	Sponsor /Collaborators	Start Date	Phases
NCT00518739	Completed	Advanced Cancer	Merck	2007-02	Phase 1
NCT00496353	Completed	Neoplasm	Merck	2007-07	Phase 1\|Phase 2

Chemical Information

Download MK-2461 SDF

Molecular Weight (MW)	495.55
Formula	C₂₄H₂₅N₅O₅S
CAS No.	917879-39-1

Storage	3 years -20â„ƒPowder
Storage	6 months-80â„ƒin DMSO
Syonnyms	N/A

Solubility (25°C) *	In vitro	DMSO	99 mg/mL (199 mM)
		Water	<1 mg/mL (<1 mM)
		Ethanol	<1 mg/mL (<1 mM)
	In vivo	1% DMSO/30% polyethylene glycol/1% Tween 80, pH 4	15 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.