Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic

Abstract

Targeted protein degradation is a rapidly exploding drug discovery strategy that uses small molecules to recruit disease-causing proteins for rapid destruction mainly via the ubiquitin–proteasome pathway. It shows great potential for treating diseases such as cancer and infectious, inflammatory, and neurodegenerative diseases, especially for those with “undruggable” pathogenic protein targets. With the recent rise of the “molecular glue” type of protein degraders, which tighten and simplify the connection of an E3 ligase with a disease-causing protein for ubiquitination and subsequent degradation, new therapies for unmet medical needs are being designed and developed. Here we use data from the CAS Content Collection and the publication landscape of recent research on targeted protein degraders to provide insights into these molecules, with a special focus on molecular glues. We also outline the advantages of the molecular glues and summarize the advances in drug discovery practices for molecular glue degraders. We further provide a thorough review of drug candidates in targeted protein degradation through E3 ligase recruitment. Finally, we highlight the progression of molecular glues in drug discovery pipelines and their targeted diseases. Overall, our paper provides a comprehensive reference to support the future development of molecular glues in medicine.

Protein–protein interfaces in molecular glue-induced ternary complexes: classification, characterization, and prediction

“…A plethora of excellent review articles on molecular glues and the complexes they stabilize have been published in the recent years, each focusing on a slightly different aspect of the topic, with the majority of them focusing on the discovery history, mechanism of action, and design strategy. [28][29][30][31][32][33][34][35][36][37] This review seeks to compile and analyze the current, published molecular glue ternary complex structures with the aim of identifying and quantifying any structural requirements for PPIs that are induced by molecular glues, as well as surveying the best computational methods to predict potential 'gluable' interfaces. To gain a general understanding of the molecular glue-induced PPI (MG-PPI), all molecular glue-induced complexes are considered, regardless of whether the molecular glue is a degrader.…”

Approaches to the Management of Metastatic Adenoid Cystic Carcinoma

“…Among ACC patients, 3/15 (20%) achieved PR and 10/15 (67%) had SD. Notably, a previous phase 2 study of everolimus alone in 34 R/M ACC patients reported no objective responses [ 88 ], suggesting that lenalidomide (and other molecular glues which act through ubiquitin E3 ligases) may have activity in ACC [ 89 ].…”

P53 upregulation by USP7-engaging molecular glues

“…Meanwhile, this may lead to possible limitations such as a "permanent" occupancy of the DUB that may in uence the DUB's function and prevent recycling of the DUB. In comparison, molecular glues are typically small chemical molecules that act on the interface between the target protein and the degradation machinery to trigger ternary complex formation 9 . They do not have separate chemical moieties interacting with each of the two proteins and the linker connecting the two moieties.…”

“…They do not have separate chemical moieties interacting with each of the two proteins and the linker connecting the two moieties. Thus, they are usually smaller and more druglike than chimeric compounds 9 . Therefore, molecular glues may exhibit advantages over DUBTACs in certain aspects.…”