Xevinapant (AT406)

製品コードS2754 バッチS275404

化学情報

	Synonyms	ARRY-334543, Debio1143, SM-406	Storage (From the date of receipt)	3 years -20°C powder 1 years -80°C in solvent
	化学式	C₃₂H₄₃N₅O₄
	分子量	561.71	CAS No.	1071992-99-8
Solubility (25°C)*	体外	DMSO	100 mg/mL (178.02 mM)
		Ethanol	100 mg/mL (178.02 mM)
		Water	Insoluble
* <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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明	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.
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]
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]

プロトコル(参考用のみ)

キナーゼアッセイ	Fluorescence Polarization Based Assays for XIAP, cIAP1, and cIAP2 BIR3 Proteins
キナーゼアッセイ	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.
細胞アッセイ	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.
動物実験	動物モデル	MDA-MB-231 xenograft tumors in severe combined immune deficiency (SCID) mice
	投薬量	10 mg/kg (i.v.), 10 mg/kg (p.o.), 30 mg/kg (p.o.) and 100 mg/kg (p.o.)
	投与方法	Administered via intravenously (i.v.) or oral gavage (p.o.)

参考

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

カスタマーフィードバック

: , , Cancer Res, 2015, 75(8):1736-48.

: , , Int J Oncol, 2016, 49(1):153-63.

: , , Biochem Biophys Res Commun, 2016, 478(1):293-9.

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

The Effect of Xevinapant Combined with Ionizing Radiation on HNSCC and Normal Tissue Cells and the Impact of Xevinapant on Its Targeted Proteins cIAP1 and XIAP [ Cells, 2023, 12(12)1653]	PubMed: 37371123
The Effect of Xevinapant Combined with Ionizing Radiation on HNSCC and Normal Tissue Cells and the Impact of Xevinapant on Its Targeted Proteins cIAP1 and XIAP [ Cells, 2023, 12(12)1653]	PubMed: 37371123
Mycoplasma hyorhinis infection promotes TNF-α signaling and SMAC mimetic-mediated apoptosis in human prostate cancer [ Heliyon, 2023, 9(10):e20655]	PubMed: 37867861
Mycoplasma hyorhinis infection promotes TNF-α signaling and SMAC mimetic-mediated apoptosis in human prostate cancer [ Heliyon, 2023, 9(10):e20655]	PubMed: 37867861
CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects [ Sci Adv, 2023, 9(33):eadf6692]	PubMed: 37595047
CD4+ T cell-mimicking nanoparticles encapsulating DIABLO/SMAC mimetics broadly neutralize HIV-1 and selectively kill HIV-1-infected cells [ Theranostics, 2021, 11(18):9009-9021]	PubMed: 34522224
Targeting c-IAP1, c-IAP2, and Bcl-2 Eliminates Senescent Glioblastoma Cells Following Temozolomide Treatment [ Cancers (Basel), 2021, 13(14)3585]	PubMed: 34298797
Smac mimetics and TRAIL cooperate to induce MLKL-dependent necroptosis in Burkitt's lymphoma cell lines [ Neoplasia, 2021, 23(5):539-550]	PubMed: 33971465
SMAC mimetics induce autophagy-dependent apoptosis of HIV-1-infected macrophages [ Cell Death Dis, 2020, 11(7):590]	PubMed: 32719312
Glucocorticoids induce differentiation and chemoresistance in ovarian cancer by promoting ROR1-mediated stemness [ Cell Death Dis, 2020, 11(9):790]	PubMed: 32989221

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

各々の製品のための特定の保管と取扱い情報は、製品データシートの上で示されます。大部分のSelleck製品は、推薦された状況の下で安定です。製品は、推薦された保管温度と異なる温度で、時々出荷されます。長期の保管のために必要とされてそれと異なる温度で、多くの製品は、短期もので安定です。品質を維持するが、夜通しの積荷のために最も経済的な貯蔵状況を用いてあなたの送料を保存する状況の下に、製品が出荷されることを、我々は確実とします。製品の受領と同時に、製品データシートの上で貯蔵推薦に従ってください。