MK-2461

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. .

CAS No. 917879-39-1

サイズ	価格(税別)	在庫状況
5mg	JPY 46800	国内在庫あり
10mg	JPY 80000	国内在庫あり

代表番号: 045-509-1970\|電子メール：[email protected] よく尋ねられる質問

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カスタマーフィードバック1个实验数据

製品安全説明書

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MK-2461関連製品

関連化合物ライブラリー	Kinase Inhibitor Library Tyrosine Kinase Inhibitor Library PI3K/Akt Inhibitor Library Cell Cycle compound library Angiogenesis Related compound Library	もっと見る

シグナル伝達経路

c-Metシグナル伝達経路

c-Met阻害剤の選択性比較

生物活性

製品説明

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. .

特性

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

c-Met (M1250T) ^[1]	c-Met (Y1235D) ^[1]	c-Met (Y1230H) ^[1]	c-Met (N1100) ^[1]	c-Met (Y1230C) ^[1]	もっとクリックする
0.4 nM	0.5 nM	1.0 nM	1.5 nM	1.5 nM	もっとクリックする

In Vitro
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]
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. ^[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.
細胞実験	細胞株	SW480, HT29, SW620, Colo 205, HCT116, HCT15, Colo 201, SCC-9, H1993, H1048, GTL-16, SNU15, et al.
	濃度	Dissolved in DMSO, final concentrations ~100 μM
	反応時間	72 hours
	実験の流れ	Cells are exposed to various concentrations of MK-2461 for 72 hours. The viability of tumor cells is measured using the ViaLight PLUS kit.

In Vivo
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]
動物実験	動物モデル	Female nude CD-1 nu/nu mice inoculated s.c. with GTL-16 cells or c-Met mutant-transformed NIH3T3 cells
	投与量	~134 mg/kg
	投与経路	Orally once or twice daily

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
臨床試験 (data from https://clinicaltrials.gov, updated on 2024-01-11)
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

参考
[1] Pan BS, et al. Cancer Res, 2010, 70(4), 1524-1533. [2] Park YW, et al. Anal Biochem, 1999, 269(1), 94-104.

参考

化学情報

分子量	495.55	化学式	C₂₄H₂₅N₅O₅S
CAS No.	917879-39-1	SDF	Download MK-2461 SDFをダウンロードする
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
保管	3年-20°C粉	溶液の保管冷凍と解凍の繰り返しを避けるため小分けにしてください	1年-80°Cin solvent
保管	3年-20°C粉	溶液の保管冷凍と解凍の繰り返しを避けるため小分けにしてください	1个月-20°Cin solvent

In vitro
Batch:

DMSO : 99 mg/mL ( (199.77 mM)；吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。)

Water : Insoluble

Ethanol : Insoluble

モル濃度計算器

in vivo
Batch:

Add solvents to the product individually and in order.

投与溶液組成計算機

実験計算

モル濃度計算器

質量	濃度	体積	分子量
=	×	×

希釈計算器分子量計算器

投与溶液組成計算機(クリア溶液)

ステップ１：実験データを入力してください。（実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します）

投与量 mg/kg 動物平均体重 g 投与体積（動物毎）μL 動物数匹

ステップ２：投与溶媒の組成を入力してください。（ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください）

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

計算結果：

投与溶媒濃度： mg/ml;

DMSOストック溶液調製方法： mg 試薬を μL DMSOに溶解する（濃度 mg/mL, 注：濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )

投与溶媒調製方法：Take μL DMSOストック溶液に μL PEG300，を加え、完全溶解後μL Tween 80，を加えて完全溶解させた後 μL ddH₂O，を加え完全に溶解させます。

投与溶媒調製方法：μL DMSOストック溶液に μL Corn oil，を加え、完全溶解。

注意：１.ストック溶液に沈殿、混濁などがないことをご確認ください；
２.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。

C1=C0/X	C1:	LOG(C1):
C2=C1/X	C2:	LOG(C2):
C3=C2/X	C3:	LOG(C3):
C4=C3/X	C4:	LOG(C4):
C5=C4/X	C5:	LOG(C5):
C6=C5/X	C6:	LOG(C6):
C7=C6/X	C7:	LOG(C7):
C8=C7/X	C8:	LOG(C8):