Macrocycles for Conventionally Druggable Targets: Lessons from Macrocyclic Kinase Inhibitors.

Macrocycles are emerging as a prominent modality in drug discovery, including for conventionally druggable targets for which simpler, acyclic ligands are readily discoverable. Given the additional synthetic challenges associated with macrocyclic chemotypes, we address what benefits macrocycles provided for these highly druggable targets. To do this, we examine the effects of macrocyclization on inhibitors of highly druggable kinase targets. For each example, we isolate closely matched acyclic/macrocyclic compound pairs, allowing us to pinpoint the effects of macrocyclization on binding affinity, selectivity, and ADME properties absent confounding factors. Our findings show that while the impact of macrocyclization on potency is variable, a profound effect on selectivity is common. Macrocyclization can also bring benefits for membrane permeability, efflux ratio, blood-brain barrier penetrance, and metabolic stability. These findings lead us to propose specific circumstances in which a drug discoverer targeting kinases or other conventionally druggable target classes should consider a macrocycle approach.