Exploring nondegrading molecular glues for protein-protein interactions

Abstract

Protein-protein interactions (PPIs) are central to cellular signaling and represent attractive, yet challenging drug targets. While molecular glue degraders (MGDs) promote target degradation via E3 ligase recruitment, nondegrading molecular glues (MGs) act independently of ubiquitination to stabilize PPIs, enabling modulation of complex assembly, localization, and signaling. In this review, we outline recent progress in nondegrading MGs, highlighting key presenter proteins, such as FKBP12, Cyclophilin A, and 14-3-3, along with emerging case studies beyond these canonical systems. Advances in chemical biology, structural analysis, and computational design are accelerating discovery in this emerging field. Collectively, these insights position nondegrading MGs as a promising therapeutic modality with distinct mechanisms and broad translational potential.

Keywords: chemically induced proximity; molecular glues; protein–protein interactions; stabilizers.