Home Apoptosis IAP inhibitor - Apoptosis related activator AZD5582 For research use only.

AZD5582

AZD5582, a novel small-molecule IAP inhibitor, binds potently to the BIR3 domains of cIAP1, cIAP2, and XIAP with IC50 values of 15, 21, and 15

AZD5582 Chemical Structure

AZD5582 Chemical Structure

CAS No. 1258392-53-8

Purity & Quality Control

AZD5582 Related Products

Signaling Pathway

IAP Signaling Pathways

IAP Signaling Pathway

Cell Data

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
MDA-MB-231 Antiproliferative assay 48 hrs Antiproliferative activity against human MDA-MB-231 cells assessed as growth inhibition after 48 hrs by Alamar Blue assay, GI50 = 0.00006 μM. 24320998
MDA-MB-231 Function assay 1 hr Binding affinity to cIAP1 in human MDA-MB-231 cells assessed as induction of protein degradation after 1 hr by ELISA, EC50 = 0.0001 μM. 24320998
MDA-MB-231 Apoptosis assay 0.5 to 1.5 nM 1 to 3 hrs Induction of apoptosis in human MDA-MB-231 cells assessed as caspase-3 cleavage at 0.5 to 1.5 nM preincubated for 1 to 3 hrs followed by compound-washout measured after 24 hrs by luciferase reporter gene assay 24320998
MDA-MB-231 Antitumor assay 0.1 to 3 mg/kg 2 weeks Antitumor activity against human MDA-MB-231 cells xenografted in CB17 SCID mouse assessed as tumor growth inhibition at 0.1 to 3 mg/kg, iv administered once a week for 2 weeks measured twice a week for 78 days 24320998
MDA-MB-231 Function assay 0.05 to 3 mg/kg 4 to 18 hrs Induction of caspase-3 cleavage in tumor of CB17 SCID mouse xenografted with human MDA-MB-231 cells at 0.05 to 3 mg/kg, iv after 4 to 18 hrs by ELISA 24320998
MDA-MB-231 Function assay 0.05 to 3 mg/kg up to 18 hrs Induction of cIAP1 degradation in tumor of CB17 SCID mouse xenografted with human MDA-MB-231 cells at 0.05 to 3 mg/kg, iv up to 18 hrs by ELISA 24320998
BT549 Growth inhibition assay Growth inhibition of human BT549 cells 24320998
MDA-MB-231 Apoptosis assay 0.5 to 1.5 nM 1 to 3 hrs Induction of apoptosis in human MDA-MB-231 cells assessed as cell death at 0.5 to 1.5 nM preincubated for 1 to 3 hrs followed by compound-washout measured after 72 hrs by MTS assay 24320998
MDA-MB-231 Function assay 1 uM 4 hrs Inhibition of XIAP-caspase-9 interaction in human MDA-MB-231 cells at 1 uM after 4 hrs by immunoprecipitation assay 24320998
MDA-MB-231 Function assay 0.03 to 1 nM 1 hr Binding affinity to cIAP2 in human MDA-MB-231 cells assessed as induction of protein degradation at 0.03 to 1 nM after 1 hr by Western blotting analysis 24320998
647V Growth inhibition assay Growth inhibition of human 647V cells 24320998
35612 Growth inhibition assay Growth inhibition of human 97-7 cells 24320998
MIAPaCa2 Growth inhibition assay Growth inhibition of human MIAPaCa2 cells 24320998
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Biological Activity

Description AZD5582, a novel small-molecule IAP inhibitor, binds potently to the BIR3 domains of cIAP1, cIAP2, and XIAP with IC50 values of 15, 21, and 15
Targets
cIAP1 [1]
(Cell-free assay)		 XIAP [1]
(Cell-free assay)		 cIAP2 [1]
(Cell-free assay)
15 nM 15 nM 21 nM
In vitro
In vitro Human pancreatic cancer cells display different sensitivities to the synthetic IAP antagonist, AZD5582. Treating human pancreatic cancer cells with AZD5582 differentially induces apoptosis, dependent on the expression of p-Akt and p-XIAP. It targets cIAP1 to induce TNF-α-induced apoptosis. AZD5582 induces a decrease of Mcl-1 protein, a member of the Bcl-2 family, but not that of Bcl-2 and Bcl-xL[1]. HNSCC (head and neck squamous cell carcinoma) cell lines SCC25, Cal27, and FaDu show a dose-dependent cytotoxic effect after treatment with AZD5582[2].
Cell Research Cell lines The human pancreatic cancer cell lines including BxPC-3, Miapaca-2, Panc-1, Panc0813, PL45, Capan-1, Capan-2 and AsPC-1
Concentrations 0, 0.01, 0.1, 0.5 μM
Incubation Time 72 h
Method

DNA or siRNA-transfected or AZD5582-treated cells are collected and cell death is determined by trypan blue exclusion using at least 200∼500 cells. For the MTS assay, pancreatic cancer cells are seeded at 1∼3 × 104 cells/well in a 96-well microtiter plate. The following day, cells are treated with AZD5582, an IAP antagonist, with various doses for 72 h. The MTS assay is performed according to the MTS assay protocol 
Experimental Result Images Methods Biomarkers Images PMID
Western blot XIAP 26314849
In Vivo
In vivo After AZD5582 treatment, tumor growth and weight decrease, whereas cleaved caspase 3 expression increases in Panc-1-derived xenograft model[1]. When administered intravenously to MDA-MB-231 xenograft-bearing mice, AZD5582 results in cIAP1 degradation and caspase-3 cleavage within tumor cells and causes substantial tumor regressions following two weekly doses of 3.0 mg/kg. Following a modest 0.5 mg/kg intravenous bolus dose of AZD5582 in mice, unbound plasma levels remain above the concentrations at which apoptosis induction and cell death are observed in MDA-MB-231 cells over the course of several hours. Although cIAP1 degradation happens very quickly upon exposure to AZD5582 in vivo, apoptosis induction (as measured by the amount of cleaved caspase-3) takes longer to reach a maximal effect. A single agent AZD5582 does not exhibit broad-based cytotoxicity but instead should be employed in selected tumor settings expected to be sensitive to IAP inhibitors or in rational combinations with other targeted therapies. The dihydrochloride salt of AZD5582 has sufficient aqueous solubility (>7 mg/mL at pH 4−6) to enable formulation for intravenous administration at the projected efficacious doses. With respect to chemical stability, AZD5582 is found to be photostable and hydrolytically stable between pH 4−6, although some amide hydrolysis is observed under strongly acidic (pH < 1) and basic (pH > 8) conditions. In addition, the compound is stable in the plasma of multiple species, with no compound degradation observed after several hours under physiological conditions[3].
Animal Research Animal Models Xenograft tumor (in Balb/c nude mice)
Dosages 3 mg/kg
Administration i.v.

Chemical Information & Solubility

Molecular Weight 1015.29 Formula

C58H78N8O8
CAS No. 1258392-53-8 SDF Download AZD5582 SDF
Smiles CC(C(=O)NC(C1CCCCC1)C(=O)N2CCCC2C(=O)NC3C(CC4=CC=CC=C34)OCC#CC#CCOC5CC6=CC=CC=C6C5NC(=O)C7CCCN7C(=O)C(C8CCCCC8)NC(=O)C(C)NC)NC
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Water : 100 mg/mL


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