ATP-competititve inhibitor of ATR



Protein target names: ATR

Mechanism of action: ATP-competititve inhibitor

Primary References:

In Vitro Validations

Uniprot ID: Q13535
Target Class: Protein kinase
Target SubClass: Atypical
Potency: Ki
Potency Value: 13 nM
PDB ID for probe-target interaction (3D structure): --
Target aliases:
Serine/threonine-protein kinase ATR, FRP1, ATR, AT ...

In Cell Validations

In Vivo Data

No in Vivo Validations

Reagent authentication certificate: PDF image

I have extra information to add

SERP ratings and comments

SERP Ratings

In Cell Rating

SERP Comments:

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 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.

(last updated: 9 May 2016 )

SERP Ratings

In Cell Rating

SERP Comments:

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.

(last updated: 20 May 2016 )

SERP Ratings

In Cell Rating

SERP 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).

(last updated: 31 May 2016 )