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 KINOME<i>scan</i> to better understand the necessity of using such a <i>full kinase panel</i> versus simply profiling one’s compound at a much smaller number of kinases, or <i>mini kinase panel</i> (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 <i>kinase hit index</i> (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 <i>average error</i>. Indeed, we identified a <i>focused MKP</i> with a 45.1% improvement in the average error (compared to random) that yields an overall correlation of <i>R</i>² = 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