GSK481

Inhibitor of RIPK1

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(0 ratings)

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Information

RIPK1

Inhibitor

10-100 nM

Probe Availability:

In Vitro Validations

Uniprot ID: Q13546

Target Class: Kinase

Target SubClass: TKL

Potency: Ki

Potency Value: 0.8 nM

Potency Assay: ADP-Glo activity assay

PDB ID for probe-target interaction (3D structure): 5HX6

Target aliases:

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

DOI Reference: 10.1021/acs.jmedchem.5b01898

In Cell Validations

In Vivo Data

No in Vivo Validations

Off-Target Selectivity Assesments

Potency assay (off target): GSK481 was tested at 10 μM in duplicate against 318 kinases in the Reaction Biology Corporation (RBC) kinase panel. Reactions were carried out at 10 μM ATP. A full list of the 318 kinases is available at http://www.reactionbiology.com. No inhibition >30% at 10 μM concentration was identified. GSK481 was tested at 10 μM in duplicate against 456 kinases (including 395 non-mutant kinases) in the DiscoveRx KINOMEscan® kinase profile panel. A full list of the 456 kinases is available at http://www.discoverx.com. ATP is not used in the KINOMEscan® competition binding assay platform. The only binding interaction identified was that of RIP1 kinase (100%); all other kinase binding interactions were <50%. Potency against RIP1 species in a fluorescence polarization (FP) assay is RIP1 human IC50 1.6 nM, RIP1 monkey IC50 2.5 nM, RIP1 rabbit IC50 2000 nM, RIP1 rat IC50 6300 nM, RIP1 mouse IC50 3200 nM, RIP1 dog IC50 7900 nM, RIP1 minipig IC50 >10,000 NM.

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SERP ratings and comments

SERP Ratings

In Cell Rating

SERP Comments:

GSK481 is a remarkably potent and selective inhibitor of RIPK1 that is suitable to interrogate this target in cells. On the other hand, it may not be suitable for in vivo use, as RIPK1 orthologs show significant divergence between primates and nonprimates that can lead to large binding differences for type I inhibitors like GSK481. Indeed, relative to the human and monkey RIPK1 orthologs, the affinity of GSK481 was at least 100x weaker in binding assays for rat, minipig, dog, rabbit and mouse orthologs of RIPK1.

(last updated: 9 Mar 2017 )

SERP Ratings

In Cell Rating

SERP Comments:

Despite being highly selective and potent, GSK481 should only be used as chemical probe in cells.

(last updated: 17 Mar 2017 )

SERP Ratings

In Cell Rating

(last updated: 21 Mar 2017 )