VE-821

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.

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.

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).