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.