XMD8-92

Reagent Authentication Certificate:

Chemical Probes Portal XMD8-92.pdf

Protein target name:

MAPK7

Mechanism of action:

ATP-competitive inhibitor

Recommended Concentration for use in cells:

1-5 uM

Probe Availability

Tocris (1234480-50-2)

MedChem Express (1234480-50-2)

MilliporeSigma (1234480-50-2)

Cayman (1234480-50-2)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

CMGC

HUGO ID:

HGNC:6880

Entrez gene ID:

5598

UNIPROT ID:

Q13164

Target alias:

BMK1, ERK4, ERK5, PRKM7

Probe Details

Chemical Probes Portal ID:

CPP119

Probe alias:

XMD 8-92

PubChem CID:

46843772

ChEMBL ID:

CHEMBL1673046

SMILES string:

CCOC1=C(C=CC(=C1)N2CCC(CC2)O)NC3=NC=C4C(=N3)N(C5=CC=CC=C5C(=O)N4C)C

InChi Key:

QAPAJIZPZGWAND-UHFFFAOYSA-N

Orthogonal probe:

AX15836BAY-885

PAINs evaluation:

Yes, but note that this is recognized as a PAIN by virtue of a p-aminotertiary aniline group and the PAINS moeity responsible is touted as an alphascreen-selective interence moeity, not a general promiscuity moiety

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

80 nM

Potency assay:

ATP-binding displacement assay

Off target activity

Potency (off target):

Off target protein and potency:

DCAMKL2 190 nMTNK1 890 nMPLK4 600 nM

Potency assay (off target):

XMD8-92 displaced ATP (>90%) at 10 uM against these related targets as well as DCAMKL1, but not for the remainder of the 402 kinases tested.

In cell validation

On target activity in cells

Potency in cells:

IC50

1.5 uM

Potency assay (cells):

Kinativ assay

Target engagement assay (cells):

Kinativ assay

Off target activity in cells

Potency in cells, off target:

IC50

Off target protein and potency (cells):

TNK1 10 uMACK1 18 uM

Potency assay, off target (cells):

Assessed XMD8-92 in Kinativ assay in HeLa cells

In vivo validation

Organism:

Sprague-Dawley rats

Dose:

2 mg/kg

Route of delivery:

Oral

Plasma half life:

2 hr

Systemic clearance:

26 mg/min/kg

Cmax:

500 nM

Tmax:

0.5 hr

Organ of Interest

Organ (O):

xenograft

Target engagement assay:

Indirect: depletion of pathway downstream of MAPK7 abrogates XMD8-92's anti-tumor activity

Primary Reference

Reference (doi):

10.1016/j.ccr.2010.08.008

Reference (PMID):

20832753

External Resources

Available data:

GDSC1

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

This compound is very selective as measured by broad profiling at DiscoverX and in a KiNativ experiment, and it blocks ERK5 in cells at about 1 micromolar. Improving the cellular activity would be a good next step.

Jun 16 2016 - 6:00pm

This compound inhibits the BET family of bromodomain-containing proteins and shouldn't be used as an ERK5 inhibitor. Substantially all of the reported biological activity for this compound derives from BET inhibition, not from ERK5 inhibition.

This compound should not be used as an ERK5 inhibitor in cellular or in vivo experiments.

Jun 17 2016 - 10:09pm

XMD8-92 is a potent and selective inhibitor of BMK1 with a KD of 80 nM. Its selectivity was determined by evaluation against a panel of 402 kinases. It has a KD of 190, 890, and 600 nM against DCAMKL2, TNK1, and PLK4, respectively. It inhibits growth factor-induced activation of BMK1 at 1 uM in HeLa cells. PK studies showed it to be orally bioavailable and having a half life of 2 hours by IV dosing. XMD8-92 was shown to be active in xenograft models with 50 mg/kg, twice daily IP dosing.

May 1 2017 - 5:30pm

XMD8-92

Probe Availability

Probe Information

Target Details

BMK1, ERK4, ERK5, PRKM7

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

External Resources

Supporting Organizations

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XMD8-92

Probe Availability

Probe Information

Target Details

BMK1, ERK4, ERK5, PRKM7

Probe Details

In vitro validation

In cell validation

In vivo validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?