PF-06263276

PF-06263276 : Inhibitor of JAK1, JAK2, JAK3, TYK2

Structure

SERP Rating

In Cells

(2 ratings)

In Model Organisms

(2 ratings)

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Probe PF-06263276 is in the process of SERP review.

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Information

JAK1
JAK2
JAK3
TYK2

Inhibitor

up to 10 uM
Reviewer recommended concentration: no higher than 300 nM

Probe Availability:

MedChemExpress

In Vitro Validations

Uniprot ID: P23458

Target Class: Kinase

Target SubClass: Tyrosine kinase

Potency: IC50

Potency Value: 2.2 nM

Potency Assay: Caliper microfluidic assays measuring the potency of inhibition of phosphorylation of a peptide substrate at 1 mM ATP concentration

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

Target aliases:

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

DOI Reference: 10.1021/acs.jmedchem.6b01634

In Cell Validations

In Vivo Data

Off-Target Selectivity Assesments

Potency assay (off target): Profiling PF-06263276 against a panel of 36 kinases at 1 μM demonstrated that it has suitable selectivity over non-JAK kinases as only JAK3 was inhibited more than 85% at this concentration. Outside target family: PF-06263276 was screened at 10 μM in a panel of receptors, transporters, enzymes, and ion channels (CEREP radioligand binding and enzyme inhibition profile), which demonstrated greater than 50% inhibition of binding or activity against a small number of targets, namely, 5-HT7, Abl kinase, acetylcholinesterase, α2B adrenergic receptor, AurA/Aur2 kinase, KDR kinase, Lck kinase, and Na+ channel.

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SERP ratings and comments

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

I would recommend caution in using higher concentrations of this compound in cells. Although the recommendations line up with the IC50s reported in Jones et al., this compound is a very potent kinase inhibitor, and higher concentrations will likely impact on additional kinases in the cell.

(last updated: 18 Jun 2023 )

SERP Ratings

In Cell Rating

In Model Organisms

SERP Comments:

While PF-06263276 clearly is a 'quality' molecule from Pfizer, it was specifically designed for inhaled delivery and properties were optimized for this route of administration (incl. e.g. high clearance!) rather than balanced profiles in cellular settings. The field of JAKis is quite advanced and there are many tool compounds available with varying family and kinome selectivity profiles including JAK1, JAK2, JAK3 and TYK2 independently, and as a group. In particular, the selectivity data for this compound is sparse with <10% of the kinome sampled and 'suitable' selectivity in the context of lung delivery can be defined in more than one way. CEREP off-target profiling is again not available in detail and 'suitable in the context of systemic exposure in the context of DPI lung delivery' does not provide the necessary level of detail from a purely cellular selectivity perspective. The published data on PF-06263276 certainly supports its use, but caution needs to be taken when interpreting data at concentrations above 100-300 nM. Without additional profiling data, this compound should only be used in the context of other available JAKis.

(last updated: 19 Jun 2023 )