GSK2830371   Click here for help

GtoPdb Ligand ID: 11103

Synonyms: compound 8 [PMID: 24390428] | GSK-2830371
Compound class: Synthetic organic
Comment: GSK2830371 is an orally active, small-molecule inhibitor of metal-dependent Ser/Thr phosphatase PPM1D [1]. Inhibition of PPM1D increases phosphorylation (inhibits dephosphorylation) of PPM1D substrates. GSK2830371 binds at an allosteric position close to PPM1D's catalytic site. Referred to as the 'flap' subdomain, this region is unique to PPM1D compared to other members of the PPM phosphatase family, and this confers PPM1D selectivity. GSK2830371 appears to be effective only in cell lines overexpressing PPM1D and with wild-type TP53 (HGNC:11998). Cell lines with mutant TP53 seem to be resistant to GSK2830371.
Click here for help

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.

✖

View interactive charts of activity data across species
2D Structure
Click here for help

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.

✖
Click here for structure editor
Physico-chemical Properties
Click here for help

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.

✖
Hydrogen bond acceptors 6
Hydrogen bond donors 3
Rotatable bonds 11
Topological polar surface area 111.36
Molecular weight 460.17
XLogP 3.63
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
Click here for help

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/)

✖
Canonical SMILES O=C([C@@H](NC(=O)c1ccc(s1)CNc1cc(Cl)cnc1C)CC1CCCC1)NC1CC1
Isomeric SMILES O=C([C@@H](NC(=O)c1ccc(s1)CNc1cc(Cl)cnc1C)CC1CCCC1)NC1CC1
InChI InChI=1S/C23H29ClN4O2S/c1-14-19(11-16(24)12-25-14)26-13-18-8-9-21(31-18)23(30)28-20(10-15-4-2-3-5-15)22(29)27-17-6-7-17/h8-9,11-12,15,17,20,26H,2-7,10,13H2,1H3,(H,27,29)(H,28,30)/t20-/m0/s1
InChI Key IVDUVEGCMXCMSO-FQEVSTJZSA-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/)
Bioactivity Comments
In tumour cell culture GSK2830371 increases phosphorylation of PPM1D substrates, and in vivo, oral administration inhibits lymphoma xenograft growth [1].
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
protein phosphatase, Mg2+/Mn2+ dependent 1D Hs Allosteric modulator Inhibition 7.1 – 7.9 pIC50 - 1-2
⤷ pIC50 7.9 (IC50 1.3x10-8 M) [1]
Description: Inhibition of dephosphorylation of Thr180 of the endogenous substrate phospho-p38 MAPK in vitro.
pIC50 7.1 (IC50 8.6x10-8 M) [2]
Description: Inhibition of PPM1D phosphatase activity determined using recombinant His-PPM1D(1-420) and a phosphorylated peptide derived from p53 as the substrate.