Synthesis and Structure-Activity Relationships of CRBN-Recruiting ZBTB11 Molecular Glue Degraders

  • J Med Chem. 2025 Sep 25;68(18):19287-19302. doi: 10.1021/acs.jmedchem.5c01352.
Jiewei Jiang  1 ,  Nathan L Tran  1  2 ,  Emma Svendsen  2 ,  Eric S Wang  2 ,  Fleur M Ferguson  1  3
Affiliations
  • 1. Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California 92093, United States.
  • 2. Center for Therapeutics Discovery, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, United States.
  • 3. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093, United States.
PMID: 40911408 DOI: 10.1021/acs.jmedchem.5c01352
Abstract

Rational optimization of molecular glue degraders (MGD) remains a challenging and lengthy process even after identification of a promising scaffold. Unlike proteolysis targeting chimeras (PROTAC), MGDs rely on induced protein-protein interactions as opposed to direct binding in order to target a protein of interest for degradation. Here, we report the synthesis of MGDs targeting the transcription factor ZBTB11 guided by protein complex modeling. Exploration of structure-activity-relationships yielded JWJ-01-306 with improved ZBTB11 degradation activity and potent antiproliferative effects against BRAF inhibitor-resistant melanoma cells. Our findings led to the discovery of a novel MGD that targets a previously undrugged transcription factor with the potential to address acquired resistance to Cancer therapy.

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