Systematic assessment of structure-promiscuity relationships between different types of kinase inhibitors

Given the increasing quest for selective kinase inhibitors, we have systematically investigated structural and structure-promiscuity relationships between promiscuous kinase inhibitors and other types with increasing potential for selective kinase inhibition. Therefore, inhibitors with different modes of action were extracted from X-ray structures of kinase complexes. For more than 18,000 promiscuous kinase inhibitors and 1253 type I¹/₂, II, and allosteric inhibitors with structurally confirmed mechanisms, analogue space was systematically charted. These inhibitors were active against a total of 426 human kinases. While nearly 80% of the promiscuous inhibitors formed related analogues series, only ~30% of other types of inhibitors were involved in such structural relationships and many of these inhibitors also had multi-kinase activity. Thus, most of the investigated type I¹/₂, II, and allosteric inhibitors with reported single-kinase activity were distinguished from promiscuous inhibitors, thus indicating potential for kinase selectivity. Structural relationships between promiscuous inhibitors and the subset of other inhibitors were organized in a matrix format including kinase activity profiles, revealing structure-promiscuity relationships for follow-up investigations.