AT406 (SM-406, ARRY-334543)

AT406 (SM-406, ARRY-334543)は一種の有効で、Smac模倣のIAP(E3ユビキチンリガーゼを通じて、役立つアポトーシス阻害剤)拮抗剤で、XIAP-BIR3、cIAP1-BIR3及びcIAP2-BIR3と結合する時のKi値が66.4 nM、1.9 nMと5.1 nMにそれぞれ分かれることですが、IAPに作用する親和力はSmac AVPIペプチドに作用する親和力より50倍-100倍が高くなります。臨床1期。

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AT406 (SM-406, ARRY-334543) 化学構造
分子量: 561.71





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製品説明 AT406 (SM-406, ARRY-334543)は一種の有効で、Smac模倣のIAP(E3ユビキチンリガーゼを通じて、役立つアポトーシス阻害剤)拮抗剤で、XIAP-BIR3、cIAP1-BIR3及びcIAP2-BIR3と結合する時のKi値が66.4 nM、1.9 nMと5.1 nMにそれぞれ分かれることですが、IAPに作用する親和力はSmac AVPIペプチドに作用する親和力より50倍-100倍が高くなります。臨床1期。
ターゲット XIAP cIAP1 cIAP2
IC50 66.4 nM (Ki) 1.9 nM (Ki) 5.1 nM (Ki) [1]
In vitro試験 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試験 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]
臨床試験 AT-406 is currently in Phase I clinical trial in patients with advanced solid tumors and lymphomas.

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

Fluorescence Polarization Based Assays for XIAP, cIAP1, and cIAP2 BIR3 Proteins 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 Kd 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 (Kd) 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 Ki value for AT-406 is calculated.

細胞アッセイ: [1]

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: [1]

動物モデル MDA-MB-231 xenograft tumors in severe combined immune deficiency (SCID) mice
製剤 HCl salt form of AT-406 in water
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.)

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)
Body Surface Area (m2)0.0070.0250.
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)



Download AT406 (SM-406, ARRY-334543) SDF
分子量 561.71


CAS No. 1071992-99-8
保管 3年-20℃
2年-80℃in solvent
溶解度 (25°C) * In vitro DMSO 100 mg/mL (178.02 mM)
Ethanol 100 mg/mL (178.02 mM)
Water <1 mg/mL
In vivo 30% propylene glycol, 5% Tween 80, 65% D5W 30 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.
化学名 (5S,8S,10aR)-N-benzhydryl-5-((S)-2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxo-decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID