AT406 (SM-406)

Catalog No.S2754

AT406 (SM-406) Chemical Structure

Molecular Weight(MW): 561.71

AT406 (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 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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Cited by 11 Publications

5 Customer Reviews

  • G, cells treated with the SM406 (1 μmol/L) for 48 hours were subjected to Western blotting.

    Cancer Res, 2015, 75(8):1736-48. . AT406 (SM-406) purchased from Selleck.

    (C) The U2OS cells were treated with TRAIL for 5 h, and with or without pre-treatment of A(AT406) for 1 h, and transient transfection with c-FLIP-siRNA for 24 h as indicated in the graph.

    Int J Oncol, 2016, 49(1):153-63. . AT406 (SM-406) purchased from Selleck.

  • AT406 is cytotoxic to human pancreatic cancer cells. Panc-1 cells (A-C), Mia-PaCa-2 cells (D), primary human pancreatic cancer cells (“Primary Pan Can”, D) or epithelial HPDE6c7 cells (D) were either left untreated (“Ctrl”, same for all figures) or stimulated with applied concentrations of AT406 (10-1000 nM) for indicated periods of time, cell survival was tested by CellTiter-Glo luminescent assay (A and D) and the clonogenic assay (B); Cell proliferation was tested by BrdU incorporation assay (C). All values were expressed as mean ± SD. For each assay, n = 5. Experiments in this figure were repeated three times, and similar results were obtained. *p < 0.05 vs. group of “Ctrl”.

    Biochem Biophys Res Commun, 2016, 478(1):293-9. . AT406 (SM-406) purchased from Selleck.

    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 (A). HepG2 cells transfected with scramble non-sense control siRNA (“NS-siRNA”) or Mcl-1 siRNA (“-1/-2”, 200 nM each, 24 hours) were stimulated with AT406 (10 μM) for indicated periods of time, Mcl-1 expression (B, upper panel); Cell viability (B, lower panel) and cell apoptosis (C) were tested. *indicated statistically significant differences as compared to “Ctrl” group. ##indicated statistically significant differences as compared to “NS-siRNA” group.

    Oncotarget, 2017, 8(6):9466-9475. AT406 (SM-406) purchased from Selleck.

  • Liposomal C6 ceramide sensitizes AT406-induced anti-pancreatic cancer activity in vivo. Panc-1 tumor bearing SCID mice (n = 10 of each group) were administrated at Day-1, 2, 3, 8, 15 and 22 with vehicle control (“Saline”), AT406 (5 mg/kg body weight, gavage) and/or plus liposomal C6 ceramide (“Lipo C6”, 25 mg/kg body weight, i.v.), tumor volumes (A), tumor daily growth (in mm3 per day, B) and mice body weights (in grams, C) were recorded; Expression of listed proteins in the xenografted tumor tissues (Day-3 after initial AT406 plus “Lipo C6” co-administration, two tumors per set) was tested by Western blot assay (D) and IHC staining assay (E, for Bcl-2). “Combine” stands for AT406 plus liposomal C6 ceramide co-administration. *p < 0.05 vs. group of “Saline”. #p < 0.05 vs. group of AT406 only. Bar = 100 μm (E).

    Biochem Biophys Res Commun, 2016, 479(2):166-172.. AT406 (SM-406) purchased from Selleck.

Purity & Quality Control

Choose Selective IAP Inhibitors

Biological Activity

Description AT406 (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 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 M3;vfGN6fG:2b4jpZ4l1gSCjc4PhfS=> NVTYSGJtPzJiaB?= NFW2V|lEgXSxdH;4bYNqfHliYXfhbY5{fCCqdX3hckB{\W6|aYTpeoUhTV[VQT3UJINmdGy|IHHzd4V{e2WmIHHzJIlvcGmkaYTpc44hd2ZiY3XscEBoem:5dHigZYZ1\XJiN{KgbJJ{KGK7IFHsZY1ieiCEbIXlJIF{e2G7LDDFR|UxRTBwMECyNUDPxE1? M1XrTlI3OjF6Mk[0
MDA-MB-231 cells MYDDfZRwfG:6aXPpeJkh[XO|YYm= M2XSbFczKGh? Mn7tR5l1d3SxeHnjbZR6KGGpYXnud5QhcHWvYX6gd4Vve2m2aY\lJG1FSS2PQj2yN|Eh[2WubIOgZZN{\XO|ZXSgZZMhcW6qaXLpeIlwdiCxZjDj[YxtKGe{b4f0bEBi\nSncjC3NkBpenNiYomgRYxidWG{IFLseYUh[XO|YYmsJGVEPTB;MD6wNVkh|ryP M1jwZVI3OjF6Mk[0
HEK293 cells NH\BTZRHfW6ldHnvckBie3OjeR?= MlPkNkBp Mnu1RY51[WexbnnzeEBi[3Srdnn0fUBifCCodXzsMYxmdme2aDDGUGFINXSjZ3fl[EBZUUGSIDj1cotvd3ewIH;ybYdqdilidILhcpNn\WO2ZXSgbY4hUEWNMkmzJINmdGy|IHHzd4V{e2WmIHHzJIlvcGmkaYTpc44hd2ZiaX70[ZJi[3Srb36ge4l1cCClYYPwZZNmKDliYX\0[ZIhOiCqcoOgZpkhcW2vdX7vdJJm[2myaYTheIlwdiCjc4PhfUwhTUN3ME2wMlA{PCEQvF2= MXyyOlIyQDJ4NB?=
human SKOV3 cells NYnnTVd4T3Kxd4ToJIlvcGmkaYTpc44h[XO|YYm= NGLXW5k1KGSjeYO= MUDHdo94fGhiaX7obYJqfGmxbjDv[kBpfW2jbjDTT29XOyClZXzsd{Bi\nSncjC0JIRigXNiYomgW3NVQCCjc4PhfUwhUUN3ME2wMlE1OiEQvF2= MnrPNlE1PDN{M{K=
MDA-MB-231 cells NFLx[FRIem:5dHigbY5pcWKrdHnvckBie3OjeR?= NVv2blNSPCCmYYnz MVHHdo94fGhiaX7obYJqfGmxbjDv[kBpfW2jbjDNSGEuVUJvMkOxJINmdGy|IHHmeIVzKDRiZHH5d{BjgSCZU2S4JIF{e2G7LDDJR|UxRTBwMUS0JO69VQ>? MYqyNVQ1OzJ|Mh?=
MDA-MB-231 cells M3vuTmZ2dmO2aX;uJIF{e2G7 MXyxMlUh|ryP NWjXU5VzOTJiaB?= MVPJcoR2[3Srb36gc4Yh[XCxcITvd4l{KGmwIHj1cYFvKE2GQT3NRk0zOzFiY3XscJMh[XO|ZYPz[YQh[XNiYXP0bZZifGmxbjDv[kBRSVKSIHPs[YF3[WenIHH0JFEvPSC3TTDh[pRmeiBzMjDodpMh[nliV3XzeIVzdiCkbH;0JIFv[Wy7c3nz MnvsNlE1PDN{M{K=

... Click to View More Cell Line Experimental Data

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]

+ Expand
  • Animal Models: MDA-MB-231 xenograft tumors in severe combined immune deficiency (SCID) mice
  • Formulation: HCl salt form of AT-406 in water
  • 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)
Ethanol 100 mg/mL (178.02 mM)
Water Insoluble
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

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IAP Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID