Routes to molecular glue degrader discovery

  • Trends Biochem Sci. 2025 Feb;50(2):134-142. doi: 10.1016/j.tibs.2024.12.006.
Yanfen Liu  1 ,  Jieyun Bai  2 ,  Dong Li  2 ,  Yong Cang  3
Affiliations
  • 1. School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China. Electronic address: [email protected].
  • 2. School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China.
  • 3. School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China. Electronic address: [email protected].
PMID: 39753433 DOI: 10.1016/j.tibs.2024.12.006
Abstract

Molecular glue degraders (MGDs) represent a unique class of targeted protein degradation (TPD) modalities. By facilitating protein-protein interactions between E3 ubiquitin ligases and neo-substrates, MGDs offer a novel approach to target previously undruggable or insufficiently drugged disease-causing proteins. Here, we present an overview of recently reported MGDs, highlighting their diverse mechanisms, and we discuss mechanism-based strategies to discover new MGDs and neo-substrates. These strategies include repurposing existing E3 ubiquitin ligase-targeting ligands, screening for novel Binders to proteins of interest, and leveraging functional genomics and quantitative proteomics to probe the MGD mechanism of action. Despite their historically serendipitous discovery, MGDs are on their way to being rationally designed to deplete undesired proteins by purposely altering the evolutionarily conserved ligase:substrate interactions.

Keywords
Cullin RING ligase (CRL); E3 ubiquitin ligase; cereblon (CRBN); neo-substrate; structure–activity relationship (SAR); targeted protein degradation (TPD).