Rational Chemical Design of Molecular Glue Degraders

Targeted protein degradation with molecular glue degraders has arisen as a powerful therapeutic modality for eliminating classically undruggable disease-causing proteins through proteasome-mediated degradation. However, we currently lack rational chemical design principles for converting protein-targeting ligands into molecular glue degraders. To overcome this challenge, we sought to identify a transposable chemical handle that would convert protein-targeting ligands into molecular degraders of their corresponding targets. Using the CDK4/6 inhibitor ribociclib as a prototype, we identified a covalent handle that, when appended to the exit vector of ribociclib, induced the proteasome-mediated degradation of…

• NS
  National Science Foundation

  Award: 2127788
• IG
  Innovative Genomics Institute
• MF
  Mark Foundation For Cancer Research
• NI
  National Institutes of Health

  Awards: S10OD024998, -0001, R01CA240981
• NI
  Novartis Institutes for BioMedical Research
• NS
  Natural Sciences and Engineering Research Council of Canada
• NC
  National Cancer Institute

  Awards: R35CA263814, R01CA240981
• DO
  Division of Chemistry

  Award: 2127788