(R)-STU104   Click here for help

GtoPdb Ligand ID: 12006

Synonyms: (R)-4e [PMID: 35442672]
Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: (R)-STU104 is a first-in-class molecule that inhibits the interaction between the proteins kinases TAK1 (mitogen-activated protein kinase kinase kinase 7; MAP3K7) and MKK3 (mitogen-activated protein kinase kinase 3; MAP2K3) [1]. These kinases are part of the inflammatory signalling cascade that culminates in TNF-α production. (R)-STU104 binds to MKK3 at a location that disrupts its interaction with the upstream kinase TAK1. This action perturbs MKK3 phosphorylation by TAK1 and inhibits downstream signal propagation. Blocking TAK1-mediated phosphorylation of MKK3 with (R)-STU104 reduces TNF-α in vitro and in mouse models of chronic ulcerative colitis (UC). In the mouse models (R)-STU104 was a more effective UC treatment than the approved UC drug mesalazine (a PPARγ inhibitor). In addition to TNF-α, (R)-STU104 reduced production of several pro-inflammatory cytokines in vivo, including IL-1β, IL-6, and IL-23.
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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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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 1
Hydrogen bond donors 0
Rotatable bonds 4
Topological polar surface area 44.76
Molecular weight 298.12
XLogP 2.81
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 COc1ccc(cc1)[C@H]1CC(=O)c2c1c(OC)cc(c2)OC
Isomeric SMILES O=C1C[C@H](c2ccc(OC)cc2)c2c(OC)cc(OC)cc12
InChI InChI=1S/C18H18O4/c1-20-12-6-4-11(5-7-12)14-10-16(19)15-8-13(21-2)9-17(22-3)18(14)15/h4-9,14H,10H2,1-3H3/t14-/m1/s1
InChI Key OYJBHGSSAJNKJF-CQSZACIVSA-N
Bioactivity Comments
(R)-STU104 decreases phosphorylation of MKK3 with an IC50 of 4 μM [1].
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
mitogen-activated protein kinase kinase 3 Hs None Binding 7.2 pKi - 1
⤷ pKi 7.2 (Ki 7.1x10-8 M) [1]
Description: Binding affinity to immobilised human MKK3 determined by SPR