Tomivosertib

Protein target name:

MKNK1, MKNK2

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

up to 1 uM

Probe Availability

MedChemExpress

Selleck Chemicals

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

CAMK

HUGO ID:

HGNC:7110 HGNC:7111

Entrez gene ID:

8569 2872

UNIPROT ID:

Q9BUB5 Q9HBH9

Target alias:

MNK1, MNK2, GPRK7

Probe Details

Chemical Probes Portal ID:

CPP2395

Probe alias:

eFT508, N45, cpd 23

PubChem CID:

118598754

ChEMBL ID:

CHEMBL4298140

SMILES string:

O=C(C1=C(C)C=C(NC2=NC=NC(N)=C2)C(N13)=O)NC43CCCCC4

InChi Key:

HKTBYUWLRDZAJK-UHFFFAOYSA-N

Physico-chemical properties

NMR:

1H NMR (500 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.68 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.97 (br, 2H), 6.42 (s, 1H), 3.00–2.90 (m, 2H), 2.43 (s, 3H), 1.80–1.60 (m, 5H), 1.5 (d, J = 24 Hz, 2H), 1.25–1.12 (m, 1H);

13C NMR (125 MHz, DMSO-d6) δ 163.8, 161.6, 159.2, 157.8, 153.4, 133.5, 121.5, 121.2, 116.6, 87.6, 78.8, 32.5, 24.2, 21.9, 13.8.

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

2.4 nM MNK1, 1 nM MNK2

Potency assay:

ADP-Glo kinase assay

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

6CK6

Structure-activity relationship:

yes

Off target activity

Potency (off target):

IC50

Off target protein and potency:

STK17A 130 nM, CLK4 790 nM

Probe Selectivity in Vitro:

Profiled for kinase selectivity at 1 uM over 400 kinases showing only 2 off-targets

In cell validation

On target activity in cells

Potency in cells:

IC50

6 nM

Potency assay (cells):

peIF4E Signaling Cellular Assay

Off target activity in cells

Probe Selectivity in Cell:

Tomivosertib did not show antiproliferative activity in a panel of solid and hematological tumor cell lines (IC50 > 30 μM), modest sensitivity (IC50 < 10 μM) was observed in a subset of DLBCL and a multiple myeloma cell line.

In vivo validation

Organism:

Mouse

Dose:

1 (IV)-10 (PO) mg/Kg

Route of delivery:

OralIntravenous

Plasma half life:

5.3 h (PO)

Systemic clearance:

33 ml/min/Kg (IV)

Cmax:

1 ug/ml (PO)

Tmax:

1 h (PO)

Vss:

2.8 L/Kg (IV)

AUC:

4 h*ug/ml (PO)

Bioavailability:

79 %

Primary Reference

Reference (doi):

10.1021/acs.jmedchem.7b01795

Reference (PMID):

29526098

Tomivosertib

Probe Availability

Probe Information

Target Details

MNK1, MNK2, GPRK7

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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Tomivosertib

Probe Availability

Probe Information

Target Details

MNK1, MNK2, GPRK7

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?