CHAPTER 8. The Properties of Kinase Inhibitors

Protein kinases are an important class of drug targets with approval of 40 drugs treating diseases in immunology, inflammation and oncology. Early enablement of parallel synthetic chemistry produced large numbers of compound sets for screening, many of which were dominated by classic sp2–sp2 coupling reactions. This resulted in relatively lipophilic molecules that had unfavorable ADME properties. With the advances in synthetic organic chemistry and kinase crystallography, medicinal chemists have the power to rationally design and synthesize potent small molecule binders of kinases in drug like chemical space. Coupled with the recent focus on efficiency, more kinase inhibitors overlap potency, selectivity and ADME. Kinases can be targeted with ATP competitive inhibitors, but the architecture of the binding pockets are dynamic and the corresponding electrostatics, size and shape of the pockets can have a big impact on small molecule properties. In addition, allosteric binding pockets present other, unique pockets with different ligand requirements. In this chapter, we explore the properties of kinase pockets and the properties of small molecules targeting different pockets of the kinase landscape. In addition, property comparisons are made from different kinase inhibitor sets, including type I and II kinase inhibitors and the most recent approved drug set.