RIPK2 inhibitor 3   Click here for help

GtoPdb Ligand ID: 10413

Synonyms: compound 3 [PMID: 31265286] | Example 1 [WO2014043446A1] | GSK2983559
PDB Ligand Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: This is an orally active RIPK2 inhibitor phosphate ester prodrug [1-2]. It is rapidly cleaved by alkaline phosphatases on contact with intestinal tissue and in whole blood. The prodrug formulation was designed to limit systemic exposure, and to focus activity at the preferred site of action in gut tissue.
A crystal structure of RIPK2 in complex with inhibitor 3 has been submitted to the PDB with ID 6RN8.
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 10
Hydrogen bond donors 3
Rotatable bonds 9
Topological polar surface area 207.26
Molecular weight 538.07
XLogP 1.49
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 OP(=O)(OCCOc1cc2ncnc(c2cc1S(=O)(=O)C(C)(C)C)Nc1ccc2c(c1)ncs2)O
Isomeric SMILES OP(=O)(OCCOc1cc2ncnc(c2cc1S(=O)(=O)C(C)(C)C)Nc1ccc2c(c1)ncs2)O
InChI InChI=1S/C21H23N4O7PS2/c1-21(2,3)35(29,30)19-9-14-15(10-17(19)31-6-7-32-33(26,27)28)22-11-23-20(14)25-13-4-5-18-16(8-13)24-12-34-18/h4-5,8-12H,6-7H2,1-3H3,(H,22,23,25)(H2,26,27,28)
InChI Key MJLYDVMFNHZMLV-UHFFFAOYSA-N
Bioactivity Comments
In a kinase screening panel VEGFR3 was identified as the only kinase to be inhibited by >90% by inhibitor 3 [2]. Screening against a range of non-kinase targets, revealed that the only receptor to be inhibited at doses <10 μM was the melatonin receptor MT3. MT3 is unlikely to represent a problematic off-target as its expression is largely restricted to the brain, and the active metabolite (RIPK2 inhibitor 5) has low brain penetration potential (in rat tissue distribution model). Inhibitor 3 does not alter hERG or CYP3A4 activity (IC50 >30 μM).

As inhibitor 3 is a prodrug, biological activity is most likely ascribed to the active metabolite which is efficiently and rapidly produced from the prodrug at the site of absorption in the gut.