Work

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

Year: 2025

Type: article

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.

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.5c01352

Authors: Jiewei Jiang, Nathan L. Tran, Emma Svendsen, Eric S. Wang, Fleur M. Ferguson

Institutions: University of California San Diego, Sanford Burnham Prebys Medical Discovery Institute

Language: English

Topic: Protein Degradation and Inhibitors

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,500