Xevinapant

SKU: orb1300488

Description

Xevinapant (Debio-1143) is a potent small molecule Smac mimetic that antagonizes IAP proteins by binding with high affinity to XIAP and cIAP. It demonstrates pro-apoptotic activity in cancer research, showing efficacy in both in vitro cellular assays and in vivo preclinical tumor models.

Research Area

Cell Biology

Key Properties

• CAS Number: 1071992-99-8
• MW: 561.71
• Purity: 99.94% (May vary between batches)
• Formula: C₃₂H₄₃N₅O₄
• SMILES: CN[C@@H](C)C(=O)N[C@H]1CN(CC[C@H]2CC[C@H](N2C1=O)C(=O)NC(c1ccccc1)c1ccccc1)C(=O)CC(C)C
• Target: Apoptosis,IAP
• Solubility: H2O:< 1 mg/mL (insoluble or slightly soluble);10% DMSO+40% PEG300+5% Tween 80+45% Saline:2 mg/mL (3.56 mM);Ethanol:93 mg/mL (165.57 mM);DMSO:127.75 mg/mL (227.43 mM)

Bioactivity

• Target IC50:
  XIAP BIR3:66.4 nM(Ki)|CIAP2-BIR3:5.1 nM(Ki)|CIAP1-BIR3:1.9 nM(Ki)
• In Vivo:
  Xevinapant has good pharmacokinetic (PK) properties and oral bioavailability in mice, rats, non-human primates, and dogs. In the MDA-MB-231 xenograft, Xevinapant 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. Xevinapant induces significant tumor growth inhibition with p of 0.0012 at 100 mg/kg.
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• In Vitro:
  Xevinapant 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. Xevinapant is more sensitive to these IAPs than Smac AVPI peptide with 50-100 fold binding affinities. Xevinapant (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, Xevinapant induces rapid cellular cIAP1 degradation and also pulls down the cellular XIAP protein. Xevinapant 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. Xevinapant induces apoptosis in MDA-MB-231 cell by inducing activation of caspase-3 and cleavage of PARP.
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• Cell Research:
  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)
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Storage & Handling

• Storage: -20°C
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

Debio-1143, Debio 1143, Debio1143, IAP, Inhibitor, mimetic, oral, ovarian, inhibit, AT 406, AT406, AT-406, ARRY334543, ARRY-334543, ARRY 334543, cancer, cIAP2-BIR3, cIAP1-BIR3, degradation, XIAP-BIR3, Xevinapant, Smac, SM406, SM-406, SM 406

Compound Identifiers

PubChem CID

25022340