A perspective on the application of macrocyclic design strategies in antitumor drugs

The macrocyclization of inhibitors has become gradually favored as a new approach for drug design in the field of anticancer agents, since the recent approvals of lorlatinib, pacritinib, and repotrectinib, and feasibility of macrocyclic modification to improve inhibitor drug-like properties has also been confirmed. Macrocycles are receiving increasing attention due to their enhanced binding affinity, target selectivity, and pharmacokinetic properties through conformational constraints. Therefore, this review summarizes various strategies for improving drug-like properties in macrocyclization and structural optimization, and reveals that macrocyclization is a new favorable strategy for drug design, aiming to provide insights for the drug discovery in different targets.