ezurpimtrostat   Click here for help

GtoPdb Ligand ID: 11991

Synonyms: GNS-561 | GNS561
Compound class: Synthetic organic
Comment: Ezurpimtrostat (GNS561) is a small molecule inhibitor of palmitoyl-protein thioesterase 1 (PPT1). It induces lysosomal dysregulation which leads to inhibition of late-stage autophagy and cell death. Antitumour, antiviral and antifibrotic activities have been demonstrated in vitro and in vivo [1-9,11].
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 4
Hydrogen bond donors 2
Rotatable bonds 6
Topological polar surface area 40.19
Molecular weight 422.22
XLogP 6.62
No. Lipinski's rules broken 1

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 Clc1ccc(cc1)CNc1cc(N2CCC(CC2)NC(C)(C)C)c2c(n1)cccc2
Isomeric SMILES CC(C)(C)NC1CCN(CC1)c1cc(nc2ccccc12)NCc1ccc(cc1)Cl
InChI InChI=1S/C25H31ClN4/c1-25(2,3)29-20-12-14-30(15-13-20)23-16-24(28-22-7-5-4-6-21(22)23)27-17-18-8-10-19(26)11-9-18/h4-11,16,20,29H,12-15,17H2,1-3H3,(H,27,28)
InChI Key QVXSJSXAVQJXOV-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. Bestion E, Jilkova ZM, Mège JL, Novello M, Kurma K, Pour STA, Lalmanach G, Vanderlynden L, Fizanne L, Bassissi F et al.. (2020)
GNS561 acts as a potent anti-fibrotic and pro-fibrolytic agent in liver fibrosis through TGF-β1 inhibition.
Ther Adv Chronic Dis, 11: 2040622320942042. [PMID:32728410]
2. Bestion E, Rachid M, Tijeras-Raballand A, Roth G, Decaens T, Ansaldi C, Mezouar S, Raymond E, Halfon P. (2024)
Ezurpimtrostat, A Palmitoyl-Protein Thioesterase-1 Inhibitor, Combined with PD-1 Inhibition Provides CD8+ Lymphocyte Repopulation in Hepatocellular Carcinoma.
Target Oncol, 19 (1): 95-106. [PMID:38133710]
3. Bestion E, Raymond E, Mezouar S, Halfon P. (2023)
Update on Autophagy Inhibitors in Cancer: Opening up to a Therapeutic Combination with Immune Checkpoint Inhibitors.
Cells, 12 (13). [PMID:37443736]
4. Bestion E, Zandi K, Belouzard S, Andreani J, Lepidi H, Novello M, Rouquairol C, Baudoin JP, Rachid M, La Scola B et al.. (2022)
GNS561 Exhibits Potent Antiviral Activity against SARS-CoV-2 through Autophagy Inhibition.
Viruses, 14 (1). DOI: 10.3390/v14010132 [PMID:35062337]
5. Brun S, Bassissi F, Serdjebi C, Novello M, Tracz J, Autelitano F, Guillemot M, Fabre P, Courcambeck J, Ansaldi C et al.. (2019)
GNS561, a new lysosomotropic small molecule, for the treatment of intrahepatic cholangiocarcinoma.
Invest New Drugs, 37 (6): 1135-1145. [PMID:30778887]
6. Brun S, Bestion E, Raymond E, Bassissi F, Jilkova ZM, Mezouar S, Rachid M, Novello M, Tracz J, Hamaï A et al.. (2022)
GNS561, a clinical-stage PPT1 inhibitor, is efficient against hepatocellular carcinoma via modulation of lysosomal functions.
Autophagy, 18 (3): 678-694. [PMID:34740311]
7. Brun S, Pascussi JM, Gifu EP, Bestion E, Macek-Jilkova Z, Wang G, Bassissi F, Mezouar S, Courcambeck J, Merle P et al.. (2021)
GNS561, a New Autophagy Inhibitor Active against Cancer Stem Cells in Hepatocellular Carcinoma and Hepatic Metastasis from Colorectal Cancer.
J Cancer, 12 (18): 5432-5438. [PMID:34405006]
8. Crissey MAS, Versace A, Bhardwaj M, Jain V, Liu S, Singh A, Beer LA, Tang HY, Villanueva J, Gimotty PA et al.. (2025)
Divergent effects of acute and chronic PPT1 inhibition in melanoma.
Autophagy, 21 (2): 394-406. [PMID:39265628]
9. Halfon P, Bestion E, Zandi K, Andreani J, Baudoin JP, La Scola B, Mege JL, Mezouar S, Schinazi RF. (2020)
GNS561 exhibits potent in vitro antiviral activity against SARS-CoV-2 through autophagy inhibition.
bioRxiv,. [PMID:33052342]
10. Harding JJ, Awada A, Roth G, Decaens T, Merle P, Kotecki N, Dreyer C, Ansaldi C, Rachid M, Mezouar S et al.. (2022)
First-In-Human Effects of PPT1 Inhibition Using the Oral Treatment with GNS561/Ezurpimtrostat in Patients with Primary and Secondary Liver Cancers.
Liver Cancer, 11 (3): 268-277. [PMID:35949290]
11. Singh S, Ahmad F, Aruri H, Das S, Parajuli P, Gavande NS, Singh PK, Kumar A. (2024)
Novel quinoline substituted autophagy inhibitors attenuate Zika virus replication in ocular cells.
Virus Res, 347: 199419. [PMID:38880335]