Small Molecule Macrocyclic Kinase Inhibitors
With over 500 family members, kinases are key mediators of many important disease relevant signaling pathways involved in cancer and immune-inflammatory diseases. Since the US FDA approval of imatinib in 2001, inhibitors of kinases are now one of the most important classes of drug molecules, covering diverse chemical scaffolds with a broad range of activity and family selectivity. Recent advances discussed in this chapter highlight the notable more recent application of macrocycles as small molecule kinase inhibitors. The potential benefits of macrocyclization are discussed in detail with highlighted case studies presented from literature studies. The key features of macrocyclic kinase inhibitors that enable them to bind specifically in ATP sites are discussed along with the different modes of inhibition. The chemical synthesis of macrocyclic kinase inhibitors is also summarized covering a surprisingly wide range of different chemistry approaches and strategies. Macrocyclic kinase inhibitors have now progressed into clinical testing where they have the potential to give additional benefit to patients. An update on clinical status is provided showing the most advanced agents may soon be approved as drug molecules.