Filgotinib

Inhibitor of JAK1

Structure

SERP Rating

In Cells

(3 ratings)

In Model Organisms

(3 ratings)

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Information

JAK1

Inhibitor

200 nM - 2 uM

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Probe Availability:

In Vitro Validations

Uniprot ID: P23458

Target Class: Kinase

Target SubClass: TK

Potency: Kd

Potency Value: 11 nM

Potency Assay: KDs were measured by displacement of a fluorescent-derivative of ATP

PDB ID for probe-target interaction (3D structure): 4P7E

Structure-activity relationship: Yes, see J Med Chem paper

Target aliases:

Tyrosine-protein kinase JAK1, JAK1B, JAK1A, JAK1, ...

DOI Reference: 10.4049/jimmunol.1201348

Uniprot ID: P23458

Target Class: Kinase

Target SubClass: TK

Potency: IC50

Potency Value: 10 nM

Potency Assay: In enzyme activity assays using recombinant enzymes

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

Target aliases:

Tyrosine-protein kinase JAK1, JAK1B, JAK1A, JAK1, ...

DOI Reference: 10.4049/jimmunol.1201348

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency end-point : IC50 JAK2 28 nM; TYK2 116 nM; JAK3 810 nM; FLT3: 338 nM, FLT4: 274 nM; CSF1R: 489 nM

Potency assay (off target): In a panel of 170 kinases at 1 uM, filgotinib had notable activity against the kinases listed below.

Probe Selectivity in Vitro:

In a panel containing 99 proteins (GPCRs, ion channels, transporters or non-kinase enzymes), no notable activity was reported. Filgotinib had no detectable impact on the activity of CYP450 enzymes (IC50>70 uM).

Potency in cells, off target : IC50 JAK2: 17.4 uM

Potency assay, off target (cells): In hERG patch clamp assay, IC50>100 uM

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

Filgotinib is one of a number of JAK inhibitors available with varying selectivity within the JAK family and across other kinases. I recommend using more than one JAK inhibitor as a tool in cellular assays. Filgotinib is reported to have geater functional selectivity for JAK1 over JAK2 in cells but biochemical selectivity is only about three-fold. Mouse pharmacokinetic data are not found in the literature.

(last updated: 30 Mar 2017 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

The probe appears to show a significant degree of selectivity of JAK1 in cellular assays. I would hence recommend this compound as a fairly selective probe for JAK1 but not for the other kinases listed as targets (JAK2, JAK3, TYK2). The compounds appears to be very selective but has "only" been screened against 170 kinases. Screening of a wider panel would build even more confidence that this compound does not inhibit other kinases. The pharmokineted (PK) data clearly show that the compound is suitable for rat and dog in vivo experiments. It may be suitable for mouse in vivo experiments as well, but I could not find any mouse PK data. I thus recommend assessing PK in mice before using it in mice.

(last updated: 11 Apr 2017 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

Filgotinib is an orally available, selective JAK1 inhibitor and is one of the best JAK inhibitors at this moment. However, the in vitro selectivity index to JAK2 is only 2.8, and the results should be interpreted with caution.

(last updated: 16 Jun 2017 )