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1071992-99-8 molecular structure
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(5S,8S,10aR)-N-(diphenylmethyl)-5-[(2S)-2-(methylamino)propanamido]-3-(3-methylbutanoyl)-6-oxo-decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide

ChemBase ID: 73303
Molecular Formular: C32H43N5O4
Molecular Mass: 561.71492
Monoisotopic Mass: 561.33150488
SMILES and InChIs

SMILES:
c1cc(ccc1)C(c1ccccc1)NC(=O)[C@@H]1CC[C@H]2N1C(=O)[C@H](CN(CC2)C(=O)CC(C)C)NC(=O)[C@H](C)NC
Canonical SMILES:
CN[C@H](C(=O)N[C@H]1CN(CC[C@@H]2N(C1=O)[C@@H](CC2)C(=O)NC(c1ccccc1)c1ccccc1)C(=O)CC(C)C)C
InChI:
InChI=1S/C32H43N5O4/c1-21(2)19-28(38)36-18-17-25-15-16-27(37(25)32(41)26(20-36)34-30(39)22(3)33-4)31(40)35-29(23-11-7-5-8-12-23)24-13-9-6-10-14-24/h5-14,21-22,25-27,29,33H,15-20H2,1-4H3,(H,34,39)(H,35,40)/t22-,25+,26-,27-/m0/s1
InChIKey:
LSXUTRRVVSPWDZ-MKKUMYSQSA-N

Cite this record

CBID:73303 http://www.chembase.cn/molecule-73303.html

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NAMES AND DATABASE IDS

NAMES AND DATABASE IDS

Names Database IDs
IUPAC name
(5S,8S,10aR)-N-(diphenylmethyl)-5-[(2S)-2-(methylamino)propanamido]-3-(3-methylbutanoyl)-6-oxo-decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
IUPAC Traditional name
(5S,8S,10aR)-N-(diphenylmethyl)-5-[(2S)-2-(methylamino)propanamido]-3-(3-methylbutanoyl)-6-oxo-octahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide
Synonyms
AT-406
CAS Number
1071992-99-8
PubChem SID
162038223
PubChem CID
25022340

DATA SOURCES

DATA SOURCES

All Sources Commercial Sources Non-commercial Sources
Data Source Data ID Price
Selleck Chemicals
S2754 external link Add to cart Please log in.
Data Source Data ID
PubChem 25022340 external link

CALCULATED PROPERTIES

CALCULATED PROPERTIES

JChem
Acid pKa 12.215752  H Acceptors
H Donor LogD (pH = 5.5) -0.6181857 
LogD (pH = 7.4) 1.0227045  Log P 2.248 
Molar Refractivity 157.0549 cm3 Polarizability 61.653313 Å3
Polar Surface Area 110.85 Å2 Rotatable Bonds
Lipinski's Rule of Five false 

PROPERTIES

PROPERTIES

Safety Information Product Information Bioassay(PubChem)
Storage Condition
-20°C expand Show data source
Salt Data
Free Base expand Show data source

DETAILS

DETAILS

Selleck Chemicals Selleck Chemicals
Selleck Chemicals - S2754 external link
Research Area
Description Cancer, Acute myeloid leukaemia
Biological Activity
Description AT-406 is a potent IAP (inhibitor of apoptosis protein) inhibitor of XIAP, cIAP1, and cIAP2 with Ki of 66.4 nM, 1.9 nM, and 5.1 nM, respectively.
Targets XIAP cIAP1 cIAP2
IC50 66.4 nM (Ki) 1.9 nM (Ki) 5.1 nM (Ki) [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]
Clinical Trials AT-406 is currently in Phase I clinical trial in patients with advanced solid tumors and lymphomas.
Features
Protocol
Kinase Assay [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.
Cell Assay [1]
Cell Lines MDA-MB-231 breast cancer and SK-OV-3 ovarian cancer cell lines
Concentrations ~ 1 μM
Incubation Time 4 days
Methods 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.
Animal Study [1]
Animal Models MDA-MB-231 xenograft tumors in severe combined immune deficiency (SCID) mice
Formulation HCl salt form of AT-406 in water
Doses 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.)
References
[1] Cai Q, et al. J Med Chem, 2011, 54(8), 2714-2726.

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