JAK3i

Irreversible inhibitor of JAK3

Structure

Information

Protein target names: JAK3

Mechanism of action: Irreversible inhibitor

In Vitro Validations

Uniprot ID: P52333
Target Class: Protein kinase
Target SubClass: TK
Potency: IC50
Potency Value: 0.43 nM
Potency Assay: JAK3 in vitro kinase assay with JAK3 kinase domain (Invitrogen), 100 uM ATP, 30 minute pre-incubation and 30 minute incubation with substrate (JAK3Tide) + 32P ATP.
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Tyrosine-protein kinase JAK3, JAK3, JAK3_HUMAN, L- ...

In Cell Validations

In Vivo Data

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SERP ratings and comments


SERP Ratings

In Cell Rating
In Model Organisms

Comments:

Broad kinase selectivity of this probe needs to be determined before it can be recommended for use. Potency data for all kinases with the structurally equivalent cysteine should be reported.

(last updated: 9 Sept 2016 )

SERP Ratings

In Cell Rating
In Model Organisms

Comments:

This is an irreversible probe that inhibits JAK3 kinase activity. Although selectivity across the kinome was not assessed, the probe exhibits very good selective for JAK3 over JAK1, JAK2 and TYK2. The probe also exhibits good selectivity over kinases with a cysteine in a similar position.

(last updated: 7 Apr 2017 )

SERP Ratings

Comments:

JAK3i is an irreversible probe molecule with good selectivity over closely related kinases. However, the paper lacks broader kinase selectivity data and this should be generated, especially for kinases with a cysteine in a structurally similar position, prior to use in cells.

(last updated: 7 Apr 2017 )

SERP Ratings

In Cell Rating
In Model Organisms

Comments:

Importantly, the in vivo effects of this probe on IL-2-driven proliferation were shown to be JAK3-dependent by using a mutant JAK3 (C905S JAK3), which exhibits similar activity to wild-type JAK3 but is not inhibited by their probe.
 

(last updated: 10 Apr 2017 )

SERP Ratings

Comments:

It would be helpful to see a more detailed selectivity assessment, but JAK3i appears reasonably selective with ~50-fold selectivity over BTK. The use of a C905S mutant to rescue demonstrates a clear JAK3-dependent effect for the compound. I would prefer further characterization of the compound to feel comfortable interpreting experimental results in any context that lacks a C905S mutant control. Additional PK/PD data would be valuable to guide use of the compound in vivo.

(last updated: 11 Apr 2017 )