Kinase-likeness and Kinase-Privileged Fragments: Toward Virtual Polypharmacology

Abstract

Small molecule protein kinase inhibitors are widely employed as biological reagents and as leads in the design of drugs for a variety of diseases. We investigated the phenomenon of kinase-likeness, i.e., the propensity of ligands to inhibit protein kinases, in the context of kinase-specific substructural fragments. The frequency of occurrence of multiple structural fragments in kinase inhibitor libraries relative to nonkinase compounds has been analyzed. A combination of structural fragment counts, termed the "2-0" kinase-likeness rule, provides approximately 5-fold enrichment in kinase active compounds. This rule has been validated using in-house kinase counterscreening data and applied prospectively to uncover kinase activities in marketed drugs. In addition, the role of discriminating fragments in kinase recognition was interrogated using available structural data, providing an insight into their effect on inhibitor potency and selectivity. One of these fragments, bisarylaniline, has been characterized as a kinase-privileged fragment with specific binding preferences and a link to increased activity within kinases.

Fragment-Based Design of Kinase Inhibitors: A Practical Guide

“…In a similar fashion, a kinase pharmacophore based on hinge binding in kinase X-ray structures was used to create a kinase-biased NMR screening library [ 39 ]. The "privileged-structure" concept was used to greatly enrich screening results for kinases by workers at Vertex [ 40 ]. Using a "kinaselikeness" parameter developed from scaffold or "framework" analysis of kinase inhibitors to select compounds for screening, gave up to a fi vefold enrichment in kinase screening experiments.…”

Measuring and interpreting the selectivity of protein kinase inhibitors

“…Measuring the selectivity and understanding the common features of the binding of unselective kinase inhibitors may help in the design of less promiscuous inhibitors or at least allow hits from screening libraries to be prioritised to select scaffolds with greater potential for specificity [7,8]. This approach may also be useful in the design of multitargeted inhibitors with controlled selectivity profiles by defining chemical classes that have a consistent bias towards a clear selectivity pattern.…”

“…The pharmacophore is suggested as a filter to remove promiscuous inhibitors from screening libraries or as the start-point for new medicinal chemistry projects. The '2-0 rule' has also been introduced to help identify likely kinase inhibitors [8]. The '2-0 rule' states that a compound is likely to have kinase activity if it contains: two or more heteroaromatic nitrogens, one or more heteroaromatic NH groups, one or more aniline and one or more nitriles.…”

Substituted 2-arylbenzothiazoles as kinase inhibitors: Hit-to-lead optimization

“…It has been questioned in the literature whether bis(hetero)arylanilines represent a privileged structure due to exerting optimal binding properties within kinases or simply due to the simplicity of synthetic access to this core fragment. 23 For Iressa, for example, the anilinic NH is not involved in hydrogen bonding and seems to serve only as an appropriate linker guaranteeing a perfect angle between the two aromatic portions. For a series of VEGFR2 and PDGFRa inhibitors, an oxygen spacer was essential and clearly favourable over NH.…”