Facilitating the development of molecular glues: Opportunities from serendipity and rational design

Molecular glues can specifically induce interactions between two or more proteins to modulate biological functions and have been proven to be a powerful therapeutic modality in drug discovery. It plays a variety of vital roles in several biological processes, such as complex stabilization, interactome modulation and transporter inhibition, thus enabling challenging therapeutic targets to be druggable. Most known molecular glues were identified serendipitously, such as IMiDs, auxin, and rapamycin. In recent years, more rational strategies were explored with the development of chemical biology and a deep understanding of the interaction between molecular glues and proteins, which led to the rational discovery of several molecular glues. Thus, in this review, we aim to highlight the discovery strategies of molecular glues from three aspects: serendipitous discovery, screening methods and rational design principles. We expect that this review will provide a reasonable reference and insights for the discovery of molecular glues.