Target‐Family‐Oriented Focused Libraries for Kinases—Conceptual Design Aspects and Commercial Availability

Parallelization and automation techniques have significantly altered the drug-discovery process over the past few years. Highly sophisticated robotic systems allow screening, processing, and analysis of the generated data sets of a million compounds within several days. Automation in the medicinal chemistry section allows the synthesis of large multipurpose screening libraries or, in turn, may provide mid-sized libraries suitable for elucidating preliminary SAR trends of hits, thus speeding up the lead identification and optimization. Nevertheless, the screening of compounds is a costly enterprise, and both the availability of sufficient protein quantities and a robust assay amenable for high throughput are prerequisites in conducting the screening of large compound numbers. Should only a limited amount of protein be available or the assay design allow only a medium throughput, a broad screening approach appears questionable, and the screening of selected compound sets instead seems favorable. Additionally, such compound arrays can be used for rapid chemical-target validation or general drugability assessments. The human kinome comprises a minimum of 518 different kinases. Undoubtedly, the kinase protein family comprises a rich source of validated targets, such as bcr-abl, EGFR, or VEGF. These enzymes play fundamental roles in many biochemical pathways, such as cell differentiation, cell-cycle control, and apoptosis. All such mechanisms are tightly regulated and entail a well-functioning and balanced counterplay of all biochemical switches involved. Upor down-regulation of individual kinases due to malfunction may result in the onset of cancer or other diseases, for example, diabetes or inflammation. However, the presence of closely related but distinct targets requires some alterations of common library-design approaches, especially in view of employing virtual descriptors and generalizing target criteria. This effort implies more than just collecting compounds derived from various structural classes. In the meantime, several companies have commercialized their focused libraries of tentative kinase inhibitors. Whereas several of these focus primarily on the established set of kinase-related scaffolds, others claim to address this matter through the design of novel scaffolds. This article will summarize conceptual approaches toward the design and the synthesis of focused libraries specifically generated to inhibit kinases, and will reflect some more recent commercial activities in this field. In general, approaches for library design are driven either by structural or by descriptor properties. In the recent past, promising approaches to designing target-family-oriented libraries have surfaced for both areas.