DEUCRAVACITINIB

DEUCRAVACITINIB : allosteric inhibitor of TYK2

Structure

SERP Rating

In Cells

(2 ratings)

In Model Organisms

(2 ratings)

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Probe DEUCRAVACITINIB is in the process of SERP review.

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Information

TYK2 (Other variant:JH2 specific)

Allosteric

up to 100 nM

Probe Availability:

MCULE

In Vitro Validations

Uniprot ID: P29597

Target Class: Kinase

Target SubClass: Tyrosine Kinase

Potency: IC50

Potency Value: 0.2 nM

Potency Assay: homogeneous time-resolved fluorescence (HTRF) binding assays measuring the displacement of a probe compound

PDB ID for probe-target interaction (3D structure): 6NZP

Target aliases:

Non-receptor tyrosine-protein kinase TYK2, TYK2, T ...

DOI Reference: 10.1021/acs.jmedchem.9b00444

Uniprot ID: P29597

Target Class: Kinase

Target SubClass: Tyrosine Kinase

Potency: Ki

Potency Value: 0.02 nM

Potency Assay: Morrison titration by varying the concentration of the fluorescent probe in the TYK2 JH2 assay

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

Target aliases:

Non-receptor tyrosine-protein kinase TYK2, TYK2, T ...

DOI Reference: 10.1021/acs.jmedchem.9b00444

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Off Target: JAK1

Potency end-point : IC50 1 nM

Potency assay (off target): Selectivity within target family: Highly specific for binding to TYK2 JH2 and does not show any significant binding affinity in the canonical TYK2, JAK1, JAK2, and JAK3 JH1 assays (IC50 values >10000 nM). Deucravacitinib s >1000-fold selective against an in-house panel of 249 protein and lipid kinases and pseudokinases, with the exception of BMPR2 (IC50 = 193 nM) and JAK1 JH2 pseudokinase domain (IC50 = 1 nM).

Probe Selectivity in Cell:

low functional activity in JAK1/JAK3 dependent IL-2 stimulated cellular assay (IC50 = 592 nM); weak potency against other JAK1-regulated pathways not dependent on TYK2, including IL-6-stimulated phosphorylation of STAT3 and IL-13-stimulated STAT6 phosphorylation; weak JAK1/JAK3 functional potency in hWB using an IL-2 stimulated STAT5 phosphorylation assay (IC50 = 1900 nM): weak JAK1/JAK2-mediated IL-6-stimulated pSTAT3 response in hWB (IC50 = 609 nM)

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

Exquisite selectivity over the other JAK family members and more broadly over the kinome. Cellular activity (IC50) is achieved below 10nM in human cells and the IC50 is 13nM in human whole blood. However, the activity against mouse whole blood is notably weaker (IC50=100nM) (see PMID: 31318208 for hWB vs mWB data) so researchers may need to use higher concentrations when working with murine cells or blood.

(last updated: 9 Feb 2023 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

Although DEUCRAVACITINIB is a highly selective and allosteric inhibitor of TYK2, a structurally related inactive control would be an additional plus. In the absence of a timely resolved PD/PD experiment, the in vivo doses and the corresponding exposures seem reasonable, although the cmax exposure is exceeding the IFNalpha hWB IC50 by more than 2 orders of magnitude.

(last updated: 20 Mar 2023 )