GNE-3511

Protein target name:

MAP3K12

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

up to 50 nM

Probe Availability

MedChemExpress

Sigma-Aldrich

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

TKL

HUGO ID:

HGNC:6851

Entrez gene ID:

7786

UNIPROT ID:

Q12852

Target alias:

DLK, MEKK12, MUK, ZPK, ZPKP1

Probe Details

Chemical Probes Portal ID:

CPP116

Probe alias:

cpd 26, 50D

PubChem CID:

72547959

ChEMBL ID:

CHEMBL3393333

SMILES string:

C1CN(CCC1C2=CC(=NC(=C2)NC3=NC=CC(=C3)C#N)N4CCC(C4)(F)F)C5COC5

InChi Key:

RHFIAUKMKYHHFA-UHFFFAOYSA-N

Physico-chemical properties

NMR:

1H NMR (400 MHz, DMSO-d6), δ: 9.72 (s, 1 H), 8.46 (s, 1 H), 8.41 (d, J = 5.0 Hz, 1 H), 7.20 (dd, J = 5.1, 1.2 Hz, 1 H), 6.60 (s, 1 H), 6.00 (s, 1 H), 4.54 (t, J = 6.4 Hz, 2 H), 4.44 (t, J = 6.0 Hz, 2 H), 3.85 (t, J = 13.2 Hz, 2 H), 3.65 (t, J = 7.2 Hz, 2 H), 3.40 (m, 1 H), 2.80 (m, 2 H), 2.56 (m, 2 H), 2.39 (m, 1 H), 1.84 (m, 2 H), 1.76−1.61 (m, 4 H).

13C NMR (126 MHz, DMSO-d6) δ 157.97, 155.37, 154.60, 152.44, 149.19, 128.44 (JCF = 245.43 Hz), 119.88, 117.38, 115.98, 113.44, 98.62, 96.98, 74.66, 58.55, 53.44 (JCF = 31.39 Hz), 49.63, 44.08, 41.64, 38.88, 33.06 (JCF = 23.66 Hz), 31.64

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

0.5 nM

Potency assay:

DLK Biochemical Assay

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

5CEO

Structure-activity relationship:

yes

Off target activity

Potency (off target):

IC50

Off target protein and potency:

JNK1 129 nMJNK3 364 nMMLK1 67.8 nMMLK2 767 nMMLK3 602 nMMKK4 > 5,000 nMMKK7 > 5,000 nM

Potency assay (off target):

GNE-3511 was assessed against 298 kinases at 0.1 uM in addition to IC50s reported above. Notable off-target activity was quantified.

In cell validation

On target activity in cells

Potency in cells:

IC50

30 nM

Potency assay (cells):

In cell substrate protein phosphorylation assay

Target engagement assay (cells):

Indirect: inhibition of protein substrate phosphorylation

In vivo validation

Organism:

Mouse, Rat, Dog, Cyno

Dose:

0.4-1 mg/kg (IV)5 mg/Kg (PO)

Route of delivery:

OralIntravenous

Plasma half life:

0.6 (M), 1.8 (R), 4 (D), 2.4 (C) h

Systemic clearance:

56 (M), 30 (R) mL/min/kg

Ratio of probe in organ to plasma (O:P):

0.24 (mouse brain), 0.7 (rat brain), 0.4 (rat CSF)

Cmax:

56 (M), 30 (R), 41(D), 16 (C) mL/min/kg

Tmax:

0.8 h (M)

Organ of Interest

Organ (O):

BrainCSF

Target engagement assay:

Indirect: inhibition of protein substrate phosphorylation in retina and substantia nigra

Primary Reference

Reference (doi):

10.1021/jm5013984 10.1021/acs.jmedchem.5b01072

Reference (PMID):

25341110 26431428

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 is a relatively promiscuous inhibitor of DLK. As indicated by the published kinome profile, many kinases are >80% inhibited at 100 nM. Care must be exercised when attributing pharmacological observations to DLK inhibitors. I would recommend using other pharmacological interventions (e.g., URMC-099) and genetic interventions to validate studies using GNE-3511.

Jul 26 2021 - 11:47am

GNE-3511 has been rigorously tested in kinase activity panels and for inhibition of closely related kinases. Biomarkers (p-c-Jun) suggest on-target activity in mouse studies.

Aug 4 2021 - 9:36pm

While this probe is a good tool for studying DLK inhibition in vitro and in vivo, there is some need to further understand selectivity, especially at higher doses and in a cellular context. Recommended concentration up to 50nM covers the IC50, but some phenotypes may require more inhibition.

Sep 7 2021 - 1:45pm

GNE-3511

Probe Availability

Probe Information

Target Details

DLK, MEKK12, MUK, ZPK, ZPKP1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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GNE-3511

Probe Availability

Probe Information

Target Details

DLK, MEKK12, MUK, ZPK, ZPKP1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?