CCT241533

Reagent Authentication Certificate:

Chemical Probes Portal CCT241533.pdf

Protein target name:

CHEK2

Mechanism of action:

ATP-competitive inhibitor

Recommended Concentration for use in cells:

500 nM - 5 uM

Probe Availability

Tocris (1262849-73-9)

MedChem Express (1262849-73-9)

Cayman (1262849-73-9)

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

CAMK

HUGO ID:

HGNC:16627

Entrez gene ID:

11200

UNIPROT ID:

O96017

Target alias:

CDS1, CHK2, HuCds1, LFS2, PP1425, RAD53, hCds1

Probe Details

Chemical Probes Portal ID:

CPP102

Probe alias:

CCT-241533, CCT 241533, GTPL8044, XBJ

PubChem CID:

49867844

ChEMBL ID:

CHEMBL1236782

SMILES string:

COC1=C(OC)C=C(C(N[C@H]2[C@H](C(C)(C)O)CNC2)=NC(C3=C(O)C=CC(F)=C3)=N4)C4=C1

InChi Key:

IXTQNANZDPZION-GSOOIIRJSA-N

PAINs evaluation:

PAINs free

Physico-chemical properties

Solubility - preferred solvent:

DMSO

Solubility - concentration:

50 mM

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

1.16 nM

Potency assay:

Radiometric assay; IC50 in kinase assay = 3 nM

Off target activity

Potency (off target):

IC50

Off target protein and potency:

CHEK1 245 nM

Potency assay (off target):

In a radiometric binding assay, 1 uM CCT241533 inhibited >80% of AHK, MARK3, GCK and MLK1 activity.

In cell validation

On target activity in cells

Potency assay (cells):

In HT-29 and HeLa cells, CCT24133 inhibited phosphorylation of CHEK2 substrates more than CHEK1 substrates.

Target engagement assay (cells):

Indirect: inhibition of protein substrate phosphorylation

In vivo validation

Organism:

mouse

Fraction of probe bound to plasma protein:

0.99

Primary Reference

Reference (doi):

10.1158/0008-5472.CAN-10-1252

Reference (PMID):

21239475

Endorsed probe

The Chemical Probes Portal endorses this compound as chemical probe for use in cells.

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

3 review(s)

SAB Members

SAB Comments

This probe has a very good selectivity profile; activity was found for only four kinases (PHK, GCK, MLKI, and MARK3) out of a panel of 85. The X-ray structure shows CCT241533 bound to CHK2 in the kinase domain region at a resolution of 2.3 Angstrom. Selectivity of CCT241533 for CHK2 over CHK1 is 80-fold. Pairing with PARP inhibitors enhances cellular toxicity. No PK data are available; solubility has been indicated in DMSO only. This probe is commercially available up to 100 mg of material, and scaled-up synthesis is possible.

Jun 30 2016 - 12:31am

CCT241533 is a potent (biochemical IC50 3 nM) and selective (63-fold vs CHK1, >90% inhibition of 3 out of 85 kinases tested at 1 uM) inhibitor of CHK2. Mechanistic inhibition of CHK2 in cancer cells (HT29) has been demonstrated at concentrations from 1 uM (J Med Chem 2011, 54(2), 580-590) and further cell activity is described (Cancer Res 2011, 71(2), 463-472) at similar concentrations.

Jun 30 2016 - 12:31am

CCT241533 is a selective, ATP-competitive CHEK2 inhibitor with biochemical (3 nM) and cellular activity. The compound also inhibits CHEK1 in vitro at 190-245 nM and potentiated the anti-proliferative effect of a PARP inhibitor in p53-minus cancer cells. The compound blocks CHEK2 autophosphorylation in response to DNA damage from bleomycin, etoposide, ionizing radiation in p53-null HT29 and HeLa cells, but not in p53 wild-type A549 cells. CCT241533 did not potentiate the cytotoxicity of bleomycin, however. The compound also blocked CHEK2 activity in three human tumor cell lines HT29 (GI50=1.7 uM), HeLa (GI50=2.2 uM) and MCF7 (GI50=5.1 uM) and protected mouse thymocytes from apoptosis by ionizing radiation.

May 23 2017 - 12:38pm

CCT241533

Probe Availability

Probe Information

Target Details

CDS1, CHK2, HuCds1, LFS2, PP1425, RAD53, hCds1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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CCT241533

Probe Availability

Probe Information

Target Details

CDS1, CHK2, HuCds1, LFS2, PP1425, RAD53, hCds1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?