ITACITINIB

ITACITINIB : Inhibitor of JAK1

Structure

SERP Rating

In Cells

(2 ratings)

In Model Organisms

(2 ratings)

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Probe ITACITINIB is in the process of SERP review.

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Information

JAK1

Inhibitor

up to 100 nM

In Vitro Validations

Uniprot ID: P23458

Target Class: Kinase

Target SubClass: Tyrosine kinase

Potency: IC50

Potency Value: 3.2 nM

Potency Assay: Biochemical assay

PDB ID for probe-target interaction (3D structure): 8BXC

Target aliases:

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

DOI Reference: 10.1016/j.ejphar.2020.173505

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay (off target): Selectivity within target family: Itacitinib was a selective JAK1 inhibitor with an IC50 value of 3.2 nM, which demonstrated 22, >600 and 256-fold selectivity over JAK2 (IC50 = 71.6 nM), JAK3 (IC50 > 2000 nM) and TYK2 (IC50 = 818 nM), respectively.

Probe Selectivity in Vitro:

At a test concentration of 100 nM, itacitinib did not show significant inhibition (<30% inhibition) of the activity of a diverse panel of 61 kinases, except for partial inhibition (40%) of JAK3.

Potency assay, off target (cells): Thrombopoietin induced STAT3 phosphorylation of PBMC: 913 ± 87 nM.

Probe Selectivity in Cell:

JAK2 specific thrombopoietin induced STAT3 phosphorylation required >10 fold higher itacitinib concentrations, further confirming the selectivity profile

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

Itacitinib is a well-characterized potent inhibitor of JAK1. Due to the small (22-fold) selectivity window between JAK1 (IC50 = 3.2 nM) and JAK2 (72 nM) inhibition I recommend to include the JAK2-selective inhibitor BMS-911543 as a control compound in your in vitro studies and carefully choose the maximal cellular concentration of itacitinib in order to avoid JAK2 effects interfering with the pharmacological readouts. The pharmacokinetics of itacitinib in mice allows BID dosing. Please note that the peak plasma concentrations and the AUC do not increase proportional with the dose.

(last updated: 19 May 2025 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

Itacitinib is a potent JAK1 inhibitor (IC50=3.2 nM @ 1mM ATP) that shows efficacy across a number of JAK1 dependent cell models and in vivo models of inflammatory diseases. While being rather selective against the JAK family members JAK3 and TYK2 (>600 and ~250-fold; biochemical assays at high ATP), selectivity against JAK2 is limited (~20 fold in biochemical assays and ~10-20 fold in cell assays). Suitable control experiments to exclude JAK2 dependent effects are recommended when using this compound as a probe, especially when employed at concentrations above 200 nM. Similarly, kinome selectivity has only been assessed in a relatively small panel (61 kinases) limiting conclusions on potential off-target kinases. The compound is orally bioavailable and shows activity across a range of rodent inflammatory disease models at oral doses between 10mg/kg once daily and 120 mg/kg twice daily dependent on the model. Oral mouse PK from 20-80mg/kg is dose dependent yet without a linear correlation. The compound can be recommended as an in vitro and in vivo chemical probe for JAK1 inhibition until a better probe becomes available. Control experiments to exclude potential off target effects are recommended.

(last updated: 5 Jul 2025 )