KU-60019

Protein target name:

ATM

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

1-10 uM

Probe Availability

Tocris (925701-49-1)

Abcam (925701-49-1)

MedChem Express (925701-46-8)

MilliporeSigma (925701-49-1)

Cayman (925701-49-1)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

Atypical

HUGO ID:

HGNC:795

Entrez gene ID:

472

UNIPROT ID:

Q13315

Target alias:

AT1, ATA, ATC, ATD, ATDC, ATE, TEL1, TELO1

Probe Details

Chemical Probes Portal ID:

CPP93

Probe alias:

Ku60019

PubChem CID:

15953870

ChEMBL ID:

CHEMBL2140173

SMILES string:

C[C@@H]1CN(C[C@@H](O1)C)CC(=O)NC2=CC3=C(C=C2)SC4=C(C=CC=C4C3)C5=CC(=O)C=C(O5)N6CCOCC6

InChi Key:

SCELLOWTHJGVIC-BGYRXZFFSA-N

PAINs evaluation:

PAINs free

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

IC50

6.3 nM

Off target activity

Potency (off target):

IC50

Off target protein and potency:

ATR >10 uMDNA-PK 1.7 uM

Potency assay (off target):

KU-60019 had little to no activity against a panel of 229 protein kinases.

In cell validation

On target activity in cells

Potency assay (cells):

Dose-dependent inhibition of protein substrate phosphorylation in U87 glioma cells

Target engagement assay (cells):

Indirect: inhibition of protein substrate phosphorylation

Primary Reference

Reference (doi):

10.1158/1535-7163.MCT-09-0519

Reference (PMID):

19808981

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 has the potential to be a useful probe for ATM. It appears to be potent in an in vitro assay with an IC50 ~6.3 nM. In a kinase panel screen (229 kinases, compound tested at 1 uM), it appears to have good selectivity. However, it should be noted that ATM was not among the kinases tested in the panel so this result should be interpreted with caution. The areas of concern for this compound are that 1) it contains a reactive motif associated with PAINS compounds (Baell & Holloway, J. Med. Chem, 2010), 2) there is a disconnect between the potency in vitro and in cells that hasn't been addressed experimentally, 3) a full dose-response curve for enzyme inhibition is not presented in the associated paper, and 4) little or no data is presented regarding direct engagement of the target in cells and overall cellular toxicity.

Jun 30 2016 - 12:36am

KU-60019, alongside the precursor KU-59933, were the prototypical inhibitors of the DNA repair kinase ATM. This compound displays enhanced solubility and selectivity against key off-targets compared to the parent compound. However, the later probe KU-59403 offers improved PK properties which are sufficient for in vivo use. This probe contains potential PAINs features, and, while evidence for selective on-target activity is reasonable, off-target screening was not extensive. This compound has largely been superseded by the clinical derivative AZD0156 and the probe compound described by the same team in J Med Chem, 2016, p6281 (AZ-5704, compound 74). However, this compound may be useful for secondary confirmation of pharmacology observed with these second-generation probes.

Jan 6 2017 - 11:56am

KU-60019 should be regarded as an unvalidated inhibitor of ATM kinase as no evidence of direct target engagement has been provided (e.g. SPR, CETSA) and although ATM kinase IC50 of 6 nM is reported the dose response curve is not shown.

KU-60019 was only counter-screened against 229 kinases (KinaseProfiler) and ATM kinase was not included in the panel to put the off-target activity into context.
This compound should not be used to draw biological conclusions about the role of ATM kinase until evidence of direct target engagement has been demonstrated and broader panel selectivity determined.

Nov 4 2020 - 11:01am

KU-60019

Probe Availability

Probe Information

Target Details

AT1, ATA, ATC, ATD, ATDC, ATE, TEL1, TELO1

Probe Details

In vitro validation

In cell validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?

Search form

KU-60019

Probe Availability

Probe Information

Target Details

AT1, ATA, ATC, ATD, ATDC, ATE, TEL1, TELO1

Probe Details

In vitro validation

In cell validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?