TAK-243

Protein target name:

UBA1

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

0.01, 0.10 or 1.00 μM

Probe Availability

MedChemExpress

Selleck Chemicals

Probe Information

Target and Probe Information

Target Details

Target class:

A1S9; A1ST; GXP1; UBE1; A1S9T; AMCX1; POC20; SMAX2; UBA1A; UBE1X; CFAP124

Probe Details

Chemical Probes Portal ID:

CPP1938

Probe alias:

MLN7243, AOB 87172, 1450833-55-2

PubChem CID:

71715374

ChEMBL ID:

CHEMBL4297405

SMILES string:

C1C(C(C(C1NC2=CC=NC3=CC(=NN23)C4=CC(=CC=C4)SC(F)(F)F)O)O)COS(=O)(=O)N

InChi Key:

KJDAGXLMHXUAGV-DGWLBADLSA-N

PAINs evaluation:

PAINS-Free

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

>75 pM

Potency assay:

E1–UBL-dependent pyrophosphate exchange (PPiX) activity

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

5TR4, 5L6J

Structure-activity relationship:

yes

Off target activity

Probe Selectivity in Vitro:

TAK-243 has weaker inhibitory activity against other closely related E1 ubiquitin-like activating enzymes such as Fat10-activating enzyme (UBA6; 7 ± 3 nM), NEDD8-activating enzyme (NAE; 28 ± 11 nM), SUMO-activating enzyme (SAE; 850 ± 180 nM), ISG15-activating enzyme (UBA7; 5,300 ± 2,100 nM) and autophagy-activating enzyme (ATG7; >10,000 nM) than it does against UAE.

In cell validation

On target activity in cells

Potency assay (cells):

CETSA, Cellular thioester assays, Lys48 immunofluorescence assay

Off target activity in cells

Probe Selectivity in Cell:

Inhibitory activities of TAK-243 (at 1 μM) against 319 kinases were measured in studies conducted at the Reaction Biology Corporation (Malvem)

Toxicity

Cytoxicity assay:

Yes

Notes on cytotoxicity:

No evidence of Cytotoxicity as reported in DOI: 10.1038/s41375-018-0167-0

In vivo validation

Organism:

Mouse

Dose:

12.5 mg/Kg18.8 mg/Kg25 mg/Kg

Route of delivery:

Subcutaneous

Plasma half life:

17.4-20.6 h

Systemic clearance:

4.99-3.89 L/h/Kg

Cmax:

3.8-6.47 uM/L

Tmax:

0.3-0.1 h

Primary Reference

Reference (doi):

10.1038/nm.4474 10.1016/j.str.2017.05.001 10.1038/s41375-018-0167-0

Reference (PMID):

29334375 28578874 29884901

TAK-243

Probe Availability

Probe Information

Target Details

A1S9; A1ST; GXP1; UBE1; A1S9T; AMCX1; POC20; SMAX2; UBA1A; UBE1X; CFAP124

Probe Details

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

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TAK-243

Probe Availability

Probe Information

Target Details

A1S9; A1ST; GXP1; UBE1; A1S9T; AMCX1; POC20; SMAX2; UBA1A; UBE1X; CFAP124

Probe Details

In vitro validation

In cell validation

Toxicity

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?