Macrocyclization in medicinal chemistry: updated strategies and applications

Abstract

Macrocyclization has emerged as a versatile design strategy in medicinal chemistry, offering unique opportunities to address limitations of conventional small molecules. By conformationally constraining ligands, macrocycles can enhance potency, selectivity, and metabolic stability, while in some cases also achieving favorable permeability and oral bioavailability. Over the past decade, applications of macrocyclization have expanded across diverse therapeutic areas, with particularly strong advances in oncology, alongside progress in immunology, inflammation, neurodegeneration, and antiviral research. Several macrocyclic agents have advanced to clinical development, and recent approvals, including daraxonrasib, highlight the translational potential of this approach. This review provides an updated synthesis of macrocyclization strategies, emphasizing their impact on potency optimization, selectivity for challenging targets, mutant-specific activity, cellular efficacy, and pharmacokinetic improvements. While macrocyclization is not universally applicable and often requires structural insights from crystallography or molecular modeling, it has become a mainstream and provide an important option in candidate optimization. By consolidating recent advances, we aim to clarify emerging design principles and highlight the future role of macrocyclization in shaping next-generation therapeutics.