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

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.

Automated summary

Targeted protein degradation is an emerging drug discovery strategy that utilizes small molecules to selectively degrade disease-causing proteins, particularly those that are difficult to target. The advent of molecular glue-type protein degraders has simplified and strengthened the connection between E3 ligases and disease-causing proteins, leading to the development of new therapies for unmet medical needs. This paper provides comprehensive insights into targeted protein degraders, with a focus on molecular glues, and discusses their advantages and the advances in drug discovery practices for these degraders.