Discovery and Structural Optimization of BRD4-Selective Monovalent Direct Degraders.

Targeted protein degradation (TPD) via the ubiquitin-proteasome system (UPS) is a rapidly advancing drug discovery strategy that enables the selective elimination of pathogenic proteins using small molecules. Here, we report the discovery of BRD4-selective monovalent direct degraders acting through DCAF11, identified by ultrahigh-throughput screening and subsequently optimized through a structure-guided medicinal chemistry campaign. Structure-activity relationship (SAR) studies support a direct degrader mechanism and culminated in the identification of the orally bioavailable compound PLX-4104. In vitro, PLX-4104 induces rapid, complete, and selective degradation of BRD4 and exhibits potent antiproliferative activity in acute myeloid leukemia (AML) models. In vivo, PLX-4104 treatment resulted in complete tumor regression in the AML MV-4-11 xenograft model. Collectively, this lays the groundwork for the rational development of monovalent direct degraders with applications extending beyond BRD4.