xevinapant   Click here for help

GtoPdb Ligand ID: 7729

Synonyms: AT 406 | AT406 | Debio-1143 | Debio1143 | QCR-136 | SM 406
Compound class: Synthetic organic
Comment: Xevinapant (formerly AT-406, Debio 1143) is an orally available inhibitor of IAPs (inhibitor of apoptosis proteins), that is in development for anticancer potential. It was initially developed by Ascenta Therapeutics, and was originally progressed by Debiopharm. Merck in-licensed the asset when it was in late stage development. Structurally, xevinapant is a small molecule SMAC mimetic; SMAC being an endogenous IAP antagonist. Inhibition of IAPs which are often overexpressed in cancer cells (blocking apoptosis) leads to cancer cell death. SMAC mimetic-induced cancer cell death appears to involve multiple pathways, including re-activation of the apoptotic pathway, and/or ubiquitin-directed degradation of IAPs, which promotes TNFα/caspase-8-induced cell death [2-3].
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 9
Hydrogen bond donors 3
Rotatable bonds 12
Topological polar surface area 110.85
Molecular weight 561.33
XLogP 3.59
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES CNC(C(=O)NC1CN(CCC2N(C1=O)C(CC2)C(=O)NC(c1ccccc1)c1ccccc1)C(=O)CC(C)C)C
Isomeric 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
InChI Key LSXUTRRVVSPWDZ-MKKUMYSQSA-N
No information available.
Summary of Clinical Use Click here for help
Xevinapant (formerly AT-406, Debio 1143) has advanced to clinical evaluation for the treatment of various tumour types. The most advanced is a Phase 3 study in patients with squamous cell carcinoma of the head and neck (as of October 2020). It is generally being tested in combination with standard of care chemo- or radiotherapies, or immunooncology biologic drugs.
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT04459715 A Study of Debio 1143 in Combination With Platinum-Based Chemotherapy and Standard Fractionation Intensity-Modulated Radiotherapy in Participants With Locally Advanced Squamous Cell Carcinoma of the Head and Neck, Suitable for Definitive Chemoradiotherapy Phase 3 Interventional Debiopharm International SA Positive results from this study were presented at the ESMO Virtual Congress 2020. The results indicated that xevinapant plus standard cisplatin-based chemoradiation therapy, reduced risk of death in high-risk patients with locally advanced head and neck cancer by 50%. Formal publication of these results is pending.
NCT04122625 Study to Assess Safety and Efficacy of the Second Mitochondrial-derived Activator of Caspases (SMAC) Mimetic Debio 1143 Phase 1/Phase 2 Interventional Debiopharm International SA
NCT03871959 Pembrolizumab In Combination With Debio 1143 In Pancreatic and Colorectal Advanced/Metastatic Adenocarcinoma Phase 1 Interventional Centre Leon Berard
NCT01078649 Dose Escalation Study of Safety and Tolerability of AT-406 in Patients With Advanced Solid Tumors and Lymphomas Phase 1 Interventional Debiopharm International SA