VX-745

Reagent Authentication Certificate:

Chemical Probes Portal VX-745.pdf

Protein target name:

MAPK14

Mechanism of action:

ATP-competitive inhibitor

Recommended Concentration for use in cells:

50-100 nM

Probe Availability

MedChem Express (209410-46-8)

Tocris (209410-46-8)

MilliporeSigma (209410-46-8)

Cayman (209410-46-8)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

CMGC

HUGO ID:

HGNC:6876

Entrez gene ID:

1432

UNIPROT ID:

Q16539

Target alias:

CSBP, CSBP1, CSBP2, CSPB1, EXIP, Mxi2, PRKM14, PRKM15, RK, SAPK2A, p38, p38ALPHA

Probe Details

Chemical Probes Portal ID:

CPP142

Probe alias:

VX745

PubChem CID:

3038525

ChEMBL ID:

CHEMBL119385

SMILES string:

C1=CC(=C(C(=C1)Cl)C2=C3C=CC(=NN3C=NC2=O)SC4=C(C=C(C=C4)F)F)Cl

InChi Key:

VEPKQEUBKLEPRA-UHFFFAOYSA-N

Orthogonal probe:

FS-694SR-318Skepinone-L

PAINs evaluation:

PAINs free

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

2.8 nM

Potency assay:

KD was determined in a kinase binding assay. The IC50 (0.009 uM) was determined using a spectrophotometric coupled-enzyme assay.

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

3FC1

Off target activity

Potency (off target):

Off target protein and potency:

MAPK11 74 nM

Potency assay (off target):

VX-745 was 20-fold selective for MAPK14 (p38alpha) > MAPK11 (p38beta) in IC50 assays. VX-745 was tested for kinase binding activity in a panel of 317 kinases showing <10 uM activity against 11 kinases (ABL1, BLK,CSF1R, DDR1, FGR, FYN, LCK, LYN, PDGFRB, SRC, YES).

In vivo validation

Organism:

BALB/c mice (Sprague-Dawley rats)

Dose:

40 mg/kg (43 mg/kg)

Route of delivery:

Oral

Plasma half life:

4.5 h (both species)

Fraction of probe bound to plasma protein:

0.23 (mouse); 0.44 (rat)

Cmax:

7.85 ug/mL (mice); 0.89 ug/mL (rat)

Primary Reference

Reference (doi):

10.1038/nbt1358 10.1021/ml2001455

Reference (PMID):

18183025 24900264

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells and in model organisms.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

This probe has a pretty good selectivity towards p38alpha with effects on peripheral blood mononuclear cells (PBMCs) and on a rheumatoid arthritis mouse model.

Jun 30 2016 - 4:44am

This is a selective probe with some off-target activity against p38β; it is able to cross the blood-brain barrier.

Jun 30 2016 - 8:17pm

Effective inhibition of p38α should be achievable at concentrations between 50-100 nM. The reported Ki for p38β is 220 nM as determined in α spectrophotometric coupled-enzyme assay using recombinant protein. The Kd for other kinases such as DDR1 is reported to be above 1000 nM.

Jul 3 2016 - 3:46pm

This compound is a fairly selective p38 MAPKα inhibitor with a 20-fold window to p38 MAPKβ based on assessement in an activity assay. It is also useful as an in vivo probe.

Jul 5 2017 - 2:56pm

VX-745

Probe Availability

Probe Information

Target Details

CSBP, CSBP1, CSBP2, CSPB1, EXIP, Mxi2, PRKM14, PRKM15, RK, SAPK2A, p38, p38ALPHA

Probe Details

In vitro validation

In vivo validation

Primary Reference

Supporting Organizations

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VX-745

Probe Availability

Probe Information

Target Details

CSBP, CSBP1, CSBP2, CSPB1, EXIP, Mxi2, PRKM14, PRKM15, RK, SAPK2A, p38, p38ALPHA

Probe Details

In vitro validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?