AT406 (SM-406)

For research use only.

Catalog No.S2754 Synonyms: ARRY-334543, Debio1143

20 publications

AT406 (SM-406) Chemical Structure

CAS No. 1071992-99-8

AT406 (SM-406, ARRY-334543, Debio1143) 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 Ki of 66.4 nM, 1.9 nM, and 5.1 nM, 50- to 100-fold higher affinities than the Smac AVPI peptide. Phase 1.

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10mM (1mL in DMSO) EUR 193 In stock
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Selleck's AT406 (SM-406) has been cited by 20 publications

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Biological Activity

Description AT406 (SM-406, ARRY-334543, Debio1143) 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 Ki of 66.4 nM, 1.9 nM, and 5.1 nM, 50- to 100-fold higher affinities than the Smac AVPI peptide. Phase 1.
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

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]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
EVSA-T cells NXTIfFBsS3m2b4TvfIlkcXS7IHHzd4F6 NG\J[|c4OiCq NIf0fGdEgXSxdH;4bYNqfHliYXfhbY5{fCCqdX3hckB{\W6|aYTpeoUhTV[VQT3UJINmdGy|IHHzd4V{e2WmIHHzJIlvcGmkaYTpc44hd2ZiY3XscEBoem:5dHigZYZ1\XJiN{KgbJJ{KGK7IFHsZY1ieiCEbIXlJIF{e2G7LDDFR|UxRTBwMECyNUDPxE1? NFfhd|IzPjJzOEK2OC=>
MDA-MB-231 cells MYrDfZRwfG:6aXPpeJkh[XO|YYm= MnHqO|IhcA>? NILOT|REgXSxdH;4bYNqfHliYXfhbY5{fCCqdX3hckB{\W6|aYTpeoUhVUSDLV3CMVI{OSClZXzsd{Bie3Onc4Pl[EBieyCrbnjpZol1cW:wIH;mJINmdGxiZ4Lve5RpKGGodHXyJFczKGi{czDifUBCdGGvYYKgRox2\SCjc4PhfUwhTUN3ME2wMlAyQSEQvF2= MnjONlYzOTh{NkS=
HEK293 cells NIPlW45HfW6ldHnvckBie3OjeR?= M17pZlIhcA>? MVrBcpRi\2:waYP0JIFkfGm4aYT5JIF1KG[3bHytcIVv\3SqIF\MRWcufGGpZ3XkJHhKSVBiKIXub45wf25ib4Lp[4lvMSC2cnHud4Zm[3SnZDDpckBJTUt{OUOgZ4VtdHNiYYPz[ZN{\WRiYYOgbY5pcWKrdHnvckBw\iCrboTldoFkfGmxbjD3bZRpKGOjc4Dhd4UhQSCjZoTldkAzKGi{czDifUBqdW23bn;wdoVkcXCrdHH0bY9vKGG|c3H5MEBGSzVyPUCuNFM1KM7:TR?= MX[yOlIyQDJ4NB?=
human SKOV3 cells MUXHdo94fGhiaX7obYJqfGmxbjDhd5NigQ>? NXHZdmlYPCCmYYnz M4XnV2dzd3e2aDDpcohq[mm2aX;uJI9nKGi3bXHuJHNMV1Z|IHPlcIx{KGGodHXyJFQh\GG7czDifUBYW1R6IHHzd4F6NCCLQ{WwQVAvOTR{IN88US=> NX;ueoI3OjF2NEOyN|I>
MDA-MB-231 cells MojnS5Jwf3SqIHnubIljcXSrb36gZZN{[Xl? NFzZVXI1KGSjeYO= NUTITIR[T3Kxd4ToJIlvcGmkaYTpc44hd2ZiaIXtZY4hVUSDLV3CMVI{OSClZXzsd{Bi\nSncjC0JIRigXNiYomgW3NVQCCjc4PhfUwhUUN3ME2wMlE1PCEQvF2= Ml\MNlE1PDN{M{K=
MDA-MB-231 cells MWjGeY5kfGmxbjDhd5NigQ>? NFTHbHQyNjVizszN NWi5TXJuOTJiaB?= MkXGTY5lfWO2aX;uJI9nKGGyb4D0c5NqeyCrbjDoeY1idiCPRFGtUWIuOjNzIHPlcIx{KGG|c3Xzd4VlKGG|IHHjeIl3[XSrb36gc4YhWEGUUDDjcIVifmGpZTDheEAyNjVidV2gZYZ1\XJiMUKgbJJ{KGK7IGfld5Rmem5iYnzveEBidmGueYPpdy=> MWeyNVQ1OzJ|Mh?=

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
cIAP-1 / XIAP / Mcl-1 / pS6K1 / Cleaved PARP ; 

PubMed: 28036295     


HepG2 cells were treated with AT406 (10 μM) or plus OSI-027 (“OSI”, 100 nM), cells were further cultured for indicated periods of time, expression of listed proteins was tested by Western blotting assay

28036295
Growth inhibition assay
Cell viability; 

PubMed: 28036295     


HepG2 cells were treated with AT406 or plus OSI-027. Cells were further cultured and subjected to MTT assay (B) or clonogenic assay (C) to evaluate cell survival. Data were means of three independent experiments ± SD (Same for all figures).

28036295
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]

Protocol

Kinase Assay:

[1]

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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.
Cell Research:

[1]

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  • Cell lines: MDA-MB-231 breast cancer and SK-OV-3 ovarian cancer cell lines
  • Concentrations: ~ 1 μM
  • Incubation Time: 4 days
  • Method:

    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.


    (Only for Reference)
Animal Research:

[1]

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  • Animal Models: MDA-MB-231 xenograft tumors in severe combined immune deficiency (SCID) mice
  • Dosages: 10 mg/kg (i.v.), 10 mg/kg (p.o.), 30 mg/kg (p.o.) and 100 mg/kg (p.o.)
  • Administration: Administered via intravenously (i.v.) or oral gavage (p.o.)
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 100 mg/mL (178.02 mM)
Water Insoluble
Ethanol '100 mg/mL
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
30% propylene glycol, 5% Tween 80, 65% D5W
For best results, use promptly after mixing.
30 mg/mL

* 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.

Chemical Information

Molecular Weight 561.71
Formula

C32H43N5O4

CAS No. 1071992-99-8
Storage powder
in solvent
Synonyms ARRY-334543, Debio1143
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

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT01265199 Terminated Drug: AT-406 in combination with daunorubicin and cytarabine Acute Myelogenous Leukemia (AML) Ascenta Therapeutics|The Leukemia and Lymphoma Society February 2011 Phase 1
NCT01078649 Completed Drug: Debio 1143 (AT-406) Cancer|Solid Tumors|Lymphoma|Malignancy Debiopharm International SA March 29 2010 Phase 1

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IAP Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID