The examples discussed above reveal that, in addition to affecting affinity for a given kinase target, macrocyclization can have differential effects on affinity for different kinases, thus affecting the target selectivity of the compound. Because kinases play such critical and diverse roles in cell signaling processes, optimization of kinase inhibitors is often driven by stringent selectivity requirements; restricting activity to just a single kinase is typically not required, but it is often important to achieve high selectivity against particular off-target kinases. Achieving selectivity is especially challenging for Type I kinase inhibitors, because the ATP binding sites that these compounds target are quite highly conserved. In principle, macrocyclization might affect selectivity in several ways. For example, the macrocycle ring itself might be constrained to a conformation that can bind to one kinase target with minimal strain but, because a small perturbation in bond lengths and angles can cause a substantial degree of strain, might bind substantially less strongly to a homologous kinase even if the binding site topology is only subtly different. Another way in which macrocyclization can affect selectivity is if cyclization preorganizes ligand atoms to make energetically favorable interactions that better exploit a difference in residues between the active site of one kinase versus another, or constrains substituents so as to cause a steric clash with a feature that is present only in the off-target(s). The literature provides examples of both of the above mechanisms for selectivity, as described below.