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.