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EN523   Click here for help

GtoPdb Ligand ID: 14445

Synonyms: EN-523
Compound class: Synthetic organic
Comment: EN523 binds to an allosteric site on the deubiquitinase enzyme OTUB1, using a reactive acrylamide warhead that interacts with non-catalytic Cys23 [3]. It functions to stabilise the protein and reduce its degradation. EN523 has been fused with ligands for other proteins to prevent their degradation as a potential therapeutic modality [1-3]. Such heterobifunctional small molecules ligands have been named deubiquitinase-targeting chimeras (DUBTACs), and have the opposite effect compared to proteolysis targeting chimeras (PROTACs) that employ a E3 ligase recruiter to enhance target protein degradation.
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 Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). 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 5
Hydrogen bond donors 0
Rotatable bonds 3
Topological polar surface area 49.85
Molecular weight 234.25
XLogP 0.23
No. Lipinski's rules broken 0

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
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.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES C=CC(=O)N1CCN(C(=O)C1)C2=CC=C(C)O2
Isomeric SMILES CC1=CC=C(O1)N2CCN(CC2=O)C(=O)C=C
InChI InChI=1S/C12H14N2O3/c1-3-10(15)13-6-7-14(11(16)8-13)12-5-4-9(2)17-12/h3-5H,1,6-8H2,2H3
InChI Key KYXPDOMFYBFXKO-UHFFFAOYSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
References
1. Cui M, Tang B, Yao T, Shao W, Zheng Q, Sun H, Hao H, Wang H, Xu X. (2026)
A Novel FXR-Targeted DUBTAC and Its Applications in Cholestasis Therapy.
J Med Chem, 69 (7): 7642-7662. [PMID:41860185]
2. Deng Z, Chen L, Qian C, Liu J, Wu Q, Song X, Xiong Y, Wang Z, Hu X, Inuzuka H et al.. (2025)
The First-In-Class Deubiquitinase-Targeting Chimera Stabilizes and Activates cGAS.
Angew Chem Int Ed Engl, 64 (3): e202415168. [PMID:39150898]
3. Henning NJ, Boike L, Spradlin JN, Ward CC, Liu G, Zhang E, Belcher BP, Brittain SM, Hesse MJ, Dovala D et al.. (2022)
Deubiquitinase-targeting chimeras for targeted protein stabilization.
Nat Chem Biol, 18 (4): 412-421. [PMID:35210618]