Rational Chemical Design of Molecular Glue Degraders

  • ACS Cent Sci. 2023 Apr 11;9(5):915-926. doi: 10.1021/acscentsci.2c01317.
Ethan S Toriki  1  2  3 ,  James W Papatzimas  1  2  3 ,  Kaila Nishikawa  1  2  3 ,  Dustin Dovala  2  4 ,  Andreas O Frank  2  4 ,  Matthew J Hesse  2  4 ,  Daniela Dankova  1  2  3 ,  Jae-Geun Song  2  4 ,  Megan Bruce-Smythe  2  4 ,  Heidi Struble  2  4 ,  Francisco J Garcia  2  5 ,  Scott M Brittain  2  5 ,  Andrew C Kile  2  4 ,  Lynn M McGregor  2  5 ,  Jeffrey M McKenna  2  5 ,  John A Tallarico  2  5 ,  Markus Schirle  2  5 ,  Daniel K Nomura  1  2  3  6
Affiliations
  • 1. Department of Chemistry, University of California, Berkeley, Berkeley, California 94720, United States.
  • 2. Novartis-Berkeley Translational Chemical Biology Institute, Berkeley, California 94720, United States.
  • 3. Innovative Genomics Institute, Berkeley, California 94704, United States.
  • 4. Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.
  • 5. Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.
  • 6. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720, United States.
PMID: 37252349 DOI: 10.1021/acscentsci.2c01317
Abstract

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 CDK4 in Cancer cells. Further modification of our initial covalent scaffold led to an improved CDK4 Degrader with the development of a but-2-ene-1,4-dione ("fumarate") handle that showed improved interactions with RNF126. Subsequent chemoproteomic profiling revealed interactions of the CDK4 Degrader and the optimized fumarate handle with RNF126 as well as additional RING-family E3 Ligases. We then transplanted this covalent handle onto a diverse set of protein-targeting ligands to induce the degradation of BRD4, Bcr-Abl and c-ABL, PDE5, AR and AR-V7, Btk, LRRK2, HDAC1/3, and SMARCA2/4. Our study undercovers a design strategy for converting protein-targeting ligands into covalent molecular glue degraders.

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