AT-406 (SM-406) (Synonyms: SM-406) |
| Catalog No.GC17448 |
AT-406 (SM-406) (AT-406) is a potent and orally bioavailable Smac mimetic and an antagonist of IAPs, and it binds to XIAP, cIAP1, and cIAP2 proteins with Ki of 66.4, 1.9, and 5.1 nM, respectively.
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1071992-99-8
Sample solution is provided at 25 µL, 10mM.
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K(i): The Ki of XIAP, cIAP1, and cIAP2 proteins is 66.4, 1.9, and 5.1 nM, respectively.
AT-406 is alsonamed as SM-406. AT-406 is a potent and orally bioavailable antagonist of multiple inhibitor of apoptosis proteins (IAPs). The inhibitor of apoptosis proteins(IAPs), originally identified in baculoviruses,are a family of apoptosis suppressor proteins which could bind and inhibit specific enzymes (caspases) such as caspase 3, 7, and 9, but not caspase 8 [1]. Growing evidence has showed that IAPs can regulateprogrammed cell death, apoptosis, cell division, cell cycle progression, and signal transduction pathways [1].
In vitro: The Ki of AT-406 against XIAP, cIAP1, and cIAP2 proteins is 66.4, 1.9, and 5.1 nM, respectively[2]. In human ovarian cancer cell lines, treatment with AT-406 for 48h could dose-dependently activate the apoptotic pathway. IC50 values of AT-406 in these ovarian cancer cells range from 0.05-0.5 μg/ml [3]. AT-406 could sensitize the response of ovarian cancer cells to carboplatin, a standard first-line chemotherapy for ovarian cancer [2].
In vivo: AT-406 exhibited good oral bioavailability in the mouse, rat, dog and non-human primates. In Rag-1 mice bearing intraperitoneally implanted OVCAR-3ip cells, AT-406 (100 mg/kg by oral gavage) significantly inhibited the progression of ovarian cancer and prolonged survival of the experimental mice both in single agent and in combination with carboplatin (40 mg/kg intraperitoneal injection) [2]. In xenograft mouse model of human breast cancer, 2-week treatment with 30 mg/kg or 100 mg/kg AT-406 effectively delayed the tumor growth [3].
Clinical trial: Oral treatment of AT-406 daily on days 1-5, initially every 14 days, later every 21 days was well tolerated at doses up to 900 mg in patients with different cancer types (Hurthle cell, melanoma, breast, rectal, hemangiopericytoma) [4].
References:
[1].Schimmer A D. Inhibitor of apoptosis proteins: translating basic knowledge into clinical practice[J]. Cancer research, 2004, 64(20): 7183-7190.
[2].Cai Q, Sun H, Peng Y, et al. A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment[J]. Journal of medicinal chemistry, 2011, 54(8): 2714-2726.
[3].Zhang T, Li Y. et al. APhysiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer. Biopharm Drug Dispos. 2013 Sep;34(6):348-59.
[4].Hurwitz HI1, Smith DC, et al. Safety, pharmacokinetics, and pharmacodynamic properties of oral DEBIO1143 (AT-406) in patients with advanced cancer: results of a first-in-man study. Cancer ChemotherPharmacol. 2015 Apr;75(4):851-9.
| Cell experiment [1]: | |
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Cell lines |
MDA-MB-231 breast cancer cell lines |
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Preparation method |
Soluble in DMSO > 27.65mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
0.1,0.3,1,3μM for 24 hours(analysis of cell death), 1.5μM for 1,3,6,12,24hours(Western blot analysis of caspase processing and cleavage of PARP (poly (ADP-ribose) polymerase)) |
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Applications |
AT-406 was a potent and orally bioavailable antagonist of multiple inhibitor of apoptosis proteins (IAPs). AT-406 effectively antagonized XIAP BIR3 (XIAP: X-linked IAP BIR3: the third BIR domain) protein, induced rapid degradation of cIAP1 (cIAP1: cellular IAP1) protein in MDA-MB-231 cell. AT-406 was effective in inhibition of cell growth in approximately 15% of more than 100 human cancer cell lines and its activity was not limited to a single tumor type. |
| Animal experiment [2]: | |
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Animal models |
SCID(severe combined immunodeficient) mice bearing human MDA-MB-231 xenograft tumor |
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Dosage form |
30 and 100mg/kg(between pH3.0 and 9.0)for oral gavage, 10mg/kg(between pH4.5 and 9.0)for intravenous administration. |
|
Application |
AT-406 could lead to the cIAP1 degradation, pro-caspase 8 decrease, CL-PARP(cleaved PARP)accumulation and tumor growth inhibition in the mouse xenograft model. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Cai Q, Sun H, Peng Y, et al. A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment[J]. Journal of medicinal chemistry, 2011, 54(8): 2714-2726. [2]. Zhang T, Li Y. et al. APhysiologically based pharmacokinetic and pharmacodynamic modeling of an antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in a mouse xenograft model of human breast cancer. Biopharm Drug Dispos. 2013 Sep;34(6):348-59. |
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| Cas No. | 1071992-99-8 | SDF | |
| Synonyms | SM-406 | ||
| Chemical Name | (5S,8S,10aR,Z)-N-benzhydryl-5-((Z)-((S)-1-hydroxy-2-(methylamino)propylidene)amino)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carbimidic acid | ||
| Canonical SMILES | CC(CC(N(C[C@@](/N=C(O)/[C@](NC)([H])C)([H])C1=O)CC[C@@](N21)([H])CC[C@@]2([H])/C(O)=N/C(C3=CC=CC=C3)C4=CC=CC=C4)=O)C | ||
| Formula | C32H43N5O4 | M.Wt | 561.71 |
| Solubility | ≥ 27.65mg/mL in DMSO | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.7803 mL | 8.9014 mL | 17.8028 mL |
| 5 mM | 0.3561 mL | 1.7803 mL | 3.5606 mL |
| 10 mM | 0.178 mL | 0.8901 mL | 1.7803 mL |
Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
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Working concentration: mg/ml;
Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid concentration mg/mL, Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug. )
Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 5 reference(s) in Google Scholar.)
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