VE-821

Reagent Authentication Certificate:

Chemical Probes Portal VE821.pdf

Protein target name:

ATR

Mechanism of action:

ATP-competititve inhibitor

Recommended Concentration for use in cells:

100 nM - 1 uM

Probe Availability

MedChem Express (1232410-49-9)

Abcam (1232410-49-9)

MilliporeSigma (1232410-49-9)

Cayman (1232410-49-9 )

Probe Information

Target and Probe Information

Target Details

Target class:

Protein kinase

Subclass:

Atypical

HUGO ID:

HGNC:882

Entrez gene ID:

545

UNIPROT ID:

Q13535

Target alias:

FCTCS, FRP1, MEC1, SCKL, SCKL1

Probe Details

Chemical Probes Portal ID:

CPP120

PubChem CID:

51000408

ChEMBL ID:

CHEMBL1766779

SMILES string:

CS(=O)(=O)C1=CC=C(C=C1)C2=CN=C(C(=N2)C(=O)NC3=CC=CC=C3)N

InChi Key:

DUIHHZKTCSNTGM-UHFFFAOYSA-N

PAINs evaluation:

PAINs free

Physico-chemical properties

NMR:

1H NMR (400 MHz, DMSO- d6): δ 10.46 (s, 1H), 9.04 (s, 1H), 8.51 (d, J = 8.5 Hz, 2H), 8.01 (d, J 8.5 Hz, 2H), 7.89 (s, 2H), 7.83 - 7.81 (m, 2H), 7.43 - 7.39 (m, 2H), 7.18 (t, J 7.3 Hz, 1H) and 3.28 (s, 3H) ppm; 13C NMR (100 MHz, DMSO- d6): δ 164.72, 155.12, 145.77, 140.98, 140.22, 138.19, 136.83, 129.00, 127.71, 126.65, 124.81, 124.68, 121.65, 43.95 ppm

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

13 nM

Off target activity

Potency (off target):

Off target protein and potency:

ATM 10 uMDNA-PK 2.2 uMMTOR >1 uMPI3Kdelta 3.9 uM

Potency assay (off target):

VE-821 was assessed against 50 kinases.

In cell validation

On target activity in cells

Potency assay (cells):

VE-821 dose-dependently inhibited ATR substrate phosphorylation in cells

Primary Reference

Reference (doi):

10.1038/nchembio.573 10.1021/jm101488z

Reference (PMID):

21490603 21413798

External Resources

Available data:

GDSC2

SAB Rating

Rating for use in Cells

3 review(s)

Rating for use in Model Organisms

no rating

SAB Members

SAB Comments

The compound has only 10 uM inhibitory activity on growth inhibition in HCT116 cells, despite low double-digit nM target potency. The aminopyrazine core is likely to be a substrate for efflux pumps. It has several off-target effects at or below this concentration. No cellular target engagement data are provided; therefore, it is assumed not to be adequately cell penetrant. Further, the aminopyrazine is likely to be mutagenic (may not matter for a probe).

Jun 16 2016 - 5:54pm

VE-821 is the first disclosed cell probe against the DNA repair target ATR and offers a useful and characterized tool against this target. Attention is drawn to the apparent disconnect between enzyme potency (13 nM) and cellular growth inhibition (10 uM). Whilst this may appear of concern, it is worth noting that such disconnects are not uncommon in DNA repair inhibitors, and this does not necessarily reflect poor physicochemical properties or poor target engagement. Rather, such assays generally require an extrinsic source of initial DNA damage to invoke the cytotoxic effect of the repair inhibitor. These data are credible and suggest limited off-target toxicity in the absence of such damage and as such, are a favorable attribute.

Jun 16 2016 - 5:56pm

VE-821 has good selectivity over the 50 or so additional kinases it was screened against. It would be great to have the kinase screening expanded to a significantly larger panel of kinases. There is a compound in http://www.ncbi.nlm.nih.gov/pubmed/21413798 that has better cell activity (420 nM) and a comparably clean kinase profile (albeit in a limited panel of 50 kinases). I don't know why Vertex published further work on VE-821 as opposed to compound 45 in this J Med Chem paper. While VE-821 has good selectivity in a relatively small kinase panel of 50 targets. If you find interesting results with this compound, it makes sense to gather broader kinase screening data to see if there are other kinase off targets that may be driving your phenotype. In addition, compound 45 in this paper appears to be more potent in cells with a comparable kinase inhibition profile.

Jun 16 2016 - 5:57pm

VE-821

Probe Availability

Probe Information

Target Details

FCTCS, FRP1, MEC1, SCKL, SCKL1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?

Search form

VE-821

Probe Availability

Probe Information

Target Details

FCTCS, FRP1, MEC1, SCKL, SCKL1

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

Primary Reference

External Resources

Supporting Organizations

Interested in supporting the portal?