Molecular glues for protein-protein interactions: Progressing toward a new dream.

The modulation of protein-protein interactions with small molecules is one of the most rapidly developing areas in drug discovery. In this review, we discuss advances over the past decade (2014–2023) focusing on molecular glues (MGs)—monovalent small molecules that induce proximity, either by stabilizing native interactions or by inducing neomorphic interactions. We include both serendipitous and rational discoveries and describe the different approaches that were used to identify them. We classify the compounds in three main categories: degradative MGs, non-degradative MGs or PPI stabilizers, and MGs that induce self-association. Diverse, illustrative examples with structural data are described in detail, emphasizing the elements of molecular recognition and cooperative binding at the interface that are fundamental for a MG mechanism of action. [Display omitted] Konstantinidou and Arkin review a decade of the evolution of molecular glues—molecules that modulate protein-protein interactions by inducing proximity. The authors emphasize key features of molecular recognition and cooperative binding, providing insights toward systematic discovery and optimization. Detailed examples highlight the diverse opportunities for molecular glues in drug discovery. [ABSTRACT FROM AUTHOR]