Macrocycles and macrocyclization in anticancer drug discovery: Important pieces of the puzzle

Increasing disease-related proteins have been identified as novel therapeutic targets. Macrocycles are emerging as potential solutions, bridging the gap between conventional small molecules and biomacromolecules in drug discovery . Inspired by successful macrocyclic drugs of natural origins, macrocycles are attracting more attention for enhanced binding affinity and target selectivity. Due to the conformation constraint and structure preorganization, macrocycles can reach bioactive conformations more easily than parent acyclic compounds . Also, rational macrocyclization combined with sequent structural modification will help improve oral bioavailability and combat drug resistance. This review introduces various strategies to enhance membrane permeability in macrocyclization and subsequent modification, such as N -methylation, intramolecular hydrogen bonding modulation, isomerization , and reversible bicyclization. Several case studies highlight macrocyclic inhibitors targeting kinases, HDAC , and protein-protein interactions. Finally, some macrocyclic agents targeting tumor microenvironments are illustrated. • Macrocycles can bridge the gap between traditional small molecules and large biomolecules. • Macrocycles in the Ro5 and beyond Ro5 chemical space may show distinctive drug-like properties. • Nature provides a rich source of macrocyclic drug candidates. • Macrocyclic compounds demonstrate outstanding potential in anti-tumor therapy. • The FDA is approving increasing macrocyclic drugs for treating human diseases.