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Rational Chemical Design of Molecular Glue Degraders

McKenna, Jeffrey, Dovala, Dustin, Frank, Andreas, Hesse, Matthew, Song, Jae, Bruce-Smythe, Megan, Struble, Heidi, Garcia, Francisco, Brittain, Scott, Kile, Drew, McGregor, Lynn, Tallarico, John, Schirle, Markus, Toriki, Ethan, Papatzimas, James, Nishikawa, Kaila, Dankova, Daniela and Nomura, Daniel (2023) Rational Chemical Design of Molecular Glue Degraders. ACS Central Science. ISSN 2374-79432374-7951


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.

Item Type: Article
Date Deposited: 31 May 2023 00:45
Last Modified: 31 May 2023 00:45