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JAK3i | JAK3i : Irreversible inhibitor of JAK3
RATINGS:
Cellular Use: (3 reviews)

In Model Organisms: (3 reviews)
Probe Summary
Selectivity
Potency
In Vivo
Control Compounds
Chemical Information
References
Vendors
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Probe Summary

Targets Biochemical/Biophysical Potency Cellular Potency
JAK3
  • IC50:0.43 nM
  • IC50:3.7 nM
Irreversible
15-250 nM

Selectivity

In Vitro Selectivity Assessment

Potency: IC50 - JAK1 1,520 nM, JAK2 8,680 nM, TYK2 >10 uM, BTK 363 nM, ITK 4,630 nM, EGFR >10 uM

Potency Assay Off-Target:
In vitro kinase assays with purified kinase domains, monitored by 32P-ATP. JAK1, JAK2, TYK2 were ass ...
Selectivity Assessment Description:
Not available
In Cell Selectivity Assessment

Potency: IC50 - BTK >10 uM, JAK1/JAK2 >10 uM, ITK/RLK 1,172 nM

Potency Assay Off-Target:
BTK: BCR-stimulated CD69 production in primary mouse splenic B cells (ibrutinib, control compound fo ...
Selectivity Assessment Description:
n/a

Potency
Cellular
In Vitro

JAK3

Mode of Action: Irreversible

Structure-Activity-Relationship data available? No

DOI Reference: 10.1038/nchembio.2056

In Vivo Validations

mouse
Dose: 40 mg/kg
Route of delivery: Intraperitoneal
Plasma half life: ~50 minutes
Organ of interest (O): Spleen, Lymph node
Target engagement assay: Overexpression of the drug resistant Cys to Ser mutant provides evidence that JAK3 binding is required for in vivo activity. Cells overexpressing C905S JAK3 were resistant to JAK3i in in vivo proliferation assays, while cells overexpressing wild-type JAK3 in the same mouse were sensitive to JAK3i. Cells in these assays came from the spleen.

DOI Reference: 10.1038/nchembio.2056

Negative Control Compounds

Compound 2 from Smith et al. 2016 (propionamide of JAK3i)

Orthogonal Probes def

TOFACITINIB
FM-381

Chemical Information

Molecular Formula C18H15FN4O3
SMILEs C=CC(=O)Nc1ccc(F)c(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
InChI InChI=1S/C18H15FN4O3/c1-3-14(24)23-10-5-6-13(19)11(7-10)16-15-12(18(25)26-4-2)8-20-17(15)22-9-21-16/h3,5-9H,1,4H2,2H3,(H,23,24)(H,20,21,22)
Molecular weight 354.11 Da
AlogP 3.065200000000001
HBond acceptors 7
HBond donors 2
Atoms 41

References

Publications

Cross References

Vendors

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Expert Reviews

by SERP
(on 9 Sept 2016 )
Cellular Use Rating
In Model Organisms
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.
by SERP
(on 7 Apr 2017 )
Cellular Use Rating
In Model Organisms
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...
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...
by SERP
(on 10 Apr 2017 )
Cellular Use Rating
In Model Organisms
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...
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...
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