Determination of a Focused Mini Kinase Panel for Early Identification of Selective Kinase Inhibitors

We analyzed an extensive data set
of 3000 Janssen kinase inhibitors
(spanning some 40 therapeutic projects) profiled at 414 kinases in
the DiscoverX KINOMEscan to better understand the
necessity of using such a full kinase panel versus
simply profiling one’s compound at a much smaller number of
kinases, or mini kinase panel (MKP), to assess its
selectivity. To this end, we generated a series of MKPs over a range
of sizes and of varying kinase membership using Monte Carlo simulations.
By defining the kinase hit index (KHI), we quantified
a compound’s selectivity based on the number of kinases it
hits. We find that certain combinations (rather than a random selection)
of kinases can result in a much lower average error. Indeed, we identified a focused MKP with a 45.1%
improvement in the average error (compared to random) that yields
an overall correlation of R2 = 0.786–0.826
for the KHI compared to the full kinase panel value. Unlike using
a full kinase panel, which is both time and cost restrictive, a focused
MKP is amenable to the triaging of all early stage compounds. In this
way, promiscuous compounds are filtered out early on, leaving the
most selective compounds for lead optimization.