BIX-02188

Assays used to discover these compounds and the cell-based assay all use firefly luciferase. While the in vitro data shows convincing activity - (nM) potency - for MEK5 inhibition with selectivity against MEK1, MEK2, and ERK1 (so these are kinase inhibitors), there should be a counterscreen to understand why the cell-based reporter assay shows a potency which is 10X weaker than what was shown with western blot data from cells.

There is limited literature surrounding BIX-02188. It is reported to be a selective inhibitor of MEK5 (Mitogen-activated protein kinases kinase, MAP2K). The MEK class of enzymes is comprised of seven total isozymes. The more ubiquitous MEK1/2 enzyme is part of the well-studied MAPK signaling cascade associated with growth factor stimulation. MEK enzymes are responsible for the phosphorylation/activation of ERK.  MEK5 activates ERK5 as a key cellular response to selected cell stressors. The initial and subsequent publications highlight the selectivity of BIX-02188 for MEK5 over MEK1/2 but selectivity versus the entire kinome is not available. That said, BIX-02188 is the only current MEK5 inhibitor known so it has value as a probe. In cell-based assays, its activity is compelling. When applied in conjunction with the ERK5 inhibitor XMD17-109, one can validate key aspects of this emerging signaling pathway with decent confidence that these small-molecule tools are properly informing on the pathway. As with any emerging agent, validation of any phenotypic effects via target knockdown is advisable. 

This report identifies two compounds, BIX02188 and BIX02189, as potent inhibitors of the kinase MEK5, and thus of the MEK/ERK pathway. The approved symbol for MEK5 is MAP2K5, so one may see this in the literature. Of the two compounds, BIX02189 appears to be slightly more potent, and perhaps slightly less selective. BIX02188 does not inhibit the closely related kinases MEK1, MEK2, ERK2, and JNK2. Both compounds show greater than 100x selectivity for 85 out of the 87 kinases they were screened against. In this enzyme panel, the closest off target is CSF1R (FMS). The compounds are active in two different cellular assays. BIX02188 can be used to probe the biology of MAP2K5 (MEK5). I would suggest the acquisition of further broad profiling data if this compound turns out to be interesting as it is used in new studies. The compound has an enamine structure, which may be unstable in protic solvents.