GSK583

ATP competitive inhibitor of RIPK2

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

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Information

RIPK2

ATP competitive inhibitor

200 nM

Probe Availability:

In Vitro Validations

Uniprot ID: O43353

Target Class: Kinase

Target SubClass: TKL

Potency: IC50

Potency Value: 5 nM

Potency Assay: A fluorescent polarization based binding assay was developed to quantitate interaction of novel test compounds at the ATP binding pocket of RIPK2 by competition with a fluorescently labeled ATP competitive ligand.

PDB ID for probe-target interaction (3D structure): 5J7B

Structure-activity relationship: See J. Med. Chem. 2016, 59, 4867−4880.

Target aliases:

Receptor-interacting serine/threonine-protein kina ...

DOI Reference: 10.1021/acs.jmedchem.6b00211

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : IC50 RIPK3 16 nM

Potency assay (off target): RIPK3: A fluorescent polarization based binding assay was developed to quantitate interaction of novel test compounds at the ATP binding pocket of RIPK3 by competition with a fluorescently labeled ATP competitive ligand.

Probe Selectivity in Vitro:

hERG: Electrophysiology; Whole cell voltage clamp technique permits investigation of the physiological role and pharmacological modulation of ion channels, transporters and receptors that link to ion channels. IC50 hERG=7.45 uM. P450 CYP3A4: Fluorescence/FLINT - Antagonism, pIC50 - Vivid Green Substrate Using Multidrop Combi Liquid Dispense, IC50 P450 CYP3A4=5 uM.

Potency assay, off target (cells): Cellular selectivity of GSK583 was evaluated in primary human monocytes. In the presence of 1 μM GSK583, NOD1- or NOD2-mediated cytokine production was completely inhibited (RIPK2-dependent pathways). In contrast, only weak inhibition was observed upon stimulation with ligands that selectively activate various TLR or cytokine receptors (RIPK2-independent pathways). The targeted receptors were stimulated with the following ligands: NOD1 (300 μg/mL, ieDAP), NOD2 (1 μg/mL, MDP), TLR2 (10 ng/mL Pam2Csk4), TLR4 (10 ng/mL, ultrapure LPS), TLR7 (10 μg/mL, gardiquimod), IL-1R (10 ng/mL, IL-1β), and TNFR (100 ng/mL, TNFα). Release of pro-inflammatory cytokines, either TNFα (NOD2, TLR2, TLR4, IL1R) or IL-8 (NOD1, TLR7, TNFR) weas measured by immunoassay.

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

(last updated: 17 Mar 2017 )

SERP Ratings

In Cell Rating

In Model Organisms

(last updated: 27 Mar 2017 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

GSK583 is a potent and selective molecule for the inhibition of RIP2 kinase, and it could be useful in probing the role of NOD1 and NOD2 in the pathogenesis of inflammatory disease. The compound has a reasonable profile for in vivo studies in rodents but falls short for human studies due to low exposure and safety concerns related to both hERG and CYP3A4.

(last updated: 29 Mar 2017 )