Xevinapant (AT406)

別名：ARRY-334543, Debio1143, SM-406

製品コード：S2754 純度：99.96%

Xevinapant (AT406, ARRY-334543, Debio1143, SM-406) is a potent Smac mimetic and an antagonist of IAP (inhibitor of apoptosis protein via E3 ubiquitin ligase), binding to XIAP-BIR3, cIAP1-BIR3 and cIAP2-BIR3 with K_i of 66.4 nM, 1.9 nM, and 5.1 nM, 50- to 100-fold higher affinities than the Smac AVPI peptide. Phase 1.

CAS No. 1071992-99-8

サイズ	価格(税別)	在庫状況
10mM (1mL in DMSO)	JPY 29500	国内在庫あり
5mg	JPY 25000	国内在庫あり
25mg	JPY 74500	国内在庫あり
1g	JPY 670500	国内在庫なし(納期7~10日)

代表番号: 045-509-1970\|電子メール：sales@selleck.co.jp よく尋ねられる質問

文献中Selleckの製品使用例（37）

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製品安全説明書

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99.96

Xevinapant (AT406)関連製品

関連ターゲット	cIAP XIAP	もっと見る
関連製品	Birinapant BV-6 LCL161 GDC-0152 AZD5582 SM-164 Tolinapant (ASTX660)	もっと見る
関連化合物ライブラリー	Autophagy Compound Library Apoptosis Compound Library Ferroptosis Compound Library Pyroptosis Compound Library Mitochondria-Targeted Compound Library	もっと見る

シグナル伝達経路

IAPシグナル伝達経路

IAP阻害剤の選択性比較

阻害剤	Citation	cIAP	XIAP	その他
Birinapant	80	++++	+
GDC-0152	22	++	++	MLXBIR3SG
Xevinapant (AT406)	37	++++	+
Tolinapant (ASTX660)	3	+++	++
AZD5582	13	+++	+++
SM-164	11		++++
Embelin	8		+	5-LO,mPGES-1
Phenoxodiol (Haginin E)	1		✔	Topo II,FLIP,Caspase
Flavokawain A	0		✔	Survivin,Bcl-xL
BV-6	70	✔
LCL161	45	✔
Berberine chloride	10	✔		Bcl-xL,Bcl-2,cytochrome c

1. "+" indicates inhibitory effect. Increased inhibition is marked by a higher "+" designation. 2. "✔" indicates inhibitory effect, but without specific value.

Cell Data

Cell Lines	Assay Type	Concentration	Incubation Time	活性情報	PMID
MDA-MB-231	Function assay	100 nM	15 mins	Induction of degradation of cIAP1 in human MDA-MB-231 cells at 100 nM after 15 mins by Western blot analysis	21443232
MDA-MB-231	Apoptosis assay	1.5 uM	12 hrs	Induction of apoptosis in human MDA-MB-231 cells assessed as activation of caspase-3 activity at 1.5 uM after 12 hrs by Western blot analysis	21443232
MDA-MB-231	Apoptosis assay	1.5 uM	12 hrs	Induction of apoptosis in human MDA-MB-231 cells assessed as activation of PARP cleavage at 1.5 uM after 12 hrs by Western blot analysis	21443232
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生物活性

製品説明

Targets

cIAP1-BIR3 ^[1] (cell-free assay)	cIAP2-BIR3 ^[1] (cell-free assay)	XIAP-BIR3 ^[1] (cell-free assay)
1.9 nM(Ki)	5.1 nM(Ki)	66.4 nM(Ki)

In Vitro
In vitro	AT-406 is a Smac mimetic and appears to mimic closely the AVPI peptide in both hydrogen bonding and hydrophobic interactions with XIAP, with additional hydrophobic contacts with W323 of XIAP. AT-406 is more sensitive to these IAPs than Smac AVPI peptide with 50-100 fold binding affinities. AT-406 (at 1 μM) completely restores the activity of caspase-9, which is suppressed by 500 nM XIAP BIR3 in a cell-free system. In MDA-MB-231 cell, AT-406 induces rapid cellular cIAP1 degradation and also pulls down the cellular XIAP protein. AT-406 effectively inhibits lots of human cancer cell lines and shows IC50 of 144 and 142 nM in MDA-MB-231 cell and SK-OV-3 ovarian cell, with low toxicity against normal-like human breast epithelial MCF-12F cells and primary human normal prostate epithelial cells. AT-406 induces apoptosis in MDA-MB-231 cell by inducing activation of caspase-3 and cleavage of PARP. ^[1]
Kinase Assay	Fluorescence Polarization Based Assays for XIAP, cIAP1, and cIAP2 BIR3 Proteins
Kinase Assay	FL-AT-406 (the fluorescently tagged AT-406) is employed to develop a set of new FP assays for determination of the binding affinities of Smac mimetics to XIAP, cIAP-1, and cIAP-2 BIR3 proteins. The K_d value of FL-AT-406 to each IAP protein is determined by titration experiments using a fixed concentration of FL-AT-406 and different concentrations of the protein up to full saturation. Fluorescence polarization values are measured using an Infinite M-1000 plate reader in Microfluor 2 96-well, black, round-bottom plates. To each well, FL-AT-406 (2, 1, and 1 nM for experiments with XIAP BIR3, cIAP-1 BIR3, and cIAP-2 BIR3, respectively) and different concentrations of the protein are added to a final volume of 125 μL in the assay buffer (100 mM potassium phosphate, pH 7.5, 100 μg/mL bovine γ-globulin, 0.02% sodium azide, with 4% DMSO). Plates are mixed and incubated at room temperature for 2-3 hours with gentle shaking. The polarization values in millipolarization units (mP) are measured at an excitation wavelength of 485 nm and an emission wavelength of 530 nm. Equilibrium dissociation constants (K_d) are then calculated by fitting the sigmoidal dose-dependent FP increases as a function of protein concentrations using Graphpad Prism 5.0 software. In competitive binding experiments for XIAP3 BIR3, AT-406 is incubated with 20 nM XIAP BIR3 protein and 2 nM FL-AT-406 in the assay buffer (100 mM potassium phosphate, pH 7.5; 100 μg/mL bovine γ-globulin; 0.02% sodium azide). In competitive binding experiments for cIAP1 BIR3 protein, 3 nM protein and 1 nM FL-AT-406 are used. In competitive binding experiments for cIAP2 BIR3, 5 nM protein and 1 nM FL-AT-406 are used. For each competitive binding experiment, polarization values are measured after 2-3 hours of incubation using an Infinite M-1000 plate reader. The IC50 value, the inhibitor concentration at which 50% of the bound tracer is displaced, is determined from the plot using nonlinear least-squares analysis. Curve fitting is performed using the PRISM software. A K_i value for AT-406 is calculated.
細胞実験	細胞株	MDA-MB-231 breast cancer and SK-OV-3 ovarian cancer cell lines
	濃度	~ 1 μM
	反応時間	4 days
	実験の流れ	Cells are seeded in 96-well flat bottom cell culture plates at a density of (3-4) × 10³ cells/well with AT-406 and incubated for 4 days. The rate of cell growth inhibition after treatment with different concentrations of AT-406 is determined by assaying with (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt (WST-8). WST-8 is added to each well to a final concentration of 10%, and then the plates are incubated at 37 °C for 2−3 hours. The absorbance of the samples is measured at 450 nm using a TECAN ULTRA reader. Concentration of AT-406 that inhibited cell growth by 50% (IC50) is calculated by comparing absorbance in the untreated cells and the cells treated with AT-406.
実験結果図	Methods	Biomarkers	結果図	PMID
	Western blot	cIAP-1 / XIAP / Mcl-1 / pS6K1 / Cleaved PARP		28036295
	Growth inhibition assay	Cell viability		28036295

In Vivo
In Vivo	AT-406 has good pharmacokinetic (PK) properties and oral bioavailability in mice, rats, non-human primates, and dogs. In the MDA-MB-231 xenograft, AT-406 effectively induces cIAP1 degradation and processing of procaspase-8, cleavage of PARP in tumor tissues at 100 mg/kg with well toleration even at 200 mg/kg. AT-406 induces significant tumor growth inhibition with p of 0.0012 at 100 mg/kg. ^[1]
動物実験	動物モデル	MDA-MB-231 xenograft tumors in severe combined immune deficiency (SCID) mice
	投与量	10 mg/kg (i.v.), 10 mg/kg (p.o.), 30 mg/kg (p.o.) and 100 mg/kg (p.o.)
	投与経路	Administered via intravenously (i.v.) or oral gavage (p.o.)

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
臨床試験 (data from https://clinicaltrials.gov, updated on 2024-05-22)
NCT01265199	Terminated	Acute Myelogenous Leukemia (AML)	Ascenta Therapeutics\|The Leukemia and Lymphoma Society	February 2011	Phase 1
NCT01078649	Completed	Cancer\|Solid Tumors\|Lymphoma\|Malignancy	Debiopharm International SA	March 29 2010	Phase 1

参考
[1] Cai Q, et al. J Med Chem, 2011, 54(8), 2714-2726.

参考

[1] Cai Q, et al. J Med Chem, 2011, 54(8), 2714-2726.

化学情報

分子量	561.71	化学式	C₃₂H₄₃N₅O₄
CAS No.	1071992-99-8	SDF	Download Xevinapant (AT406) SDFをダウンロードする
Smiles	CC(C)CC(=O)N1CCC2CCC(N2C(=O)C(C1)NC(=O)C(C)NC)C(=O)NC(C3=CC=CC=C3)C4=CC=CC=C4
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ケ月-20°Cin solvent

In vitro
Batch:

DMSO : 112 mg/mL ( (199.39 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。)

Ethanol : 112 mg/mL

Water : 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

Clear solution

30%propylene glycol 1 5%Tween 80 Click to order 2 65%D5W

30.0mg/ml (53.41mM)

Taking the 1 mL working solution as an example, add 300 μL of 100 mg/ml clarified propylene glycol stock solution to 50 μL of Tween 80, mix evenly to clarify it; then continue to add 650 μL of D5W to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.

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。

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