MassIVE MSV000094973

Partial Public PXD052975

Discovery of Monovalent Direct Degraders of BRD4 That Act Via the Recruitment of DCAF11

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Description

Targeted protein degradation (TPD) using the ubiquitin proteasome system (UPS) is a rapidly growing drug discovery modality to eliminate pathogenic proteins. Strategies for TPD have focused on heterobifunctional degraders that often suffer from poor drug-like properties, and molecular glues that rely on serendipitous discovery. Monovalent direct degraders represent an alternative approach, in which small molecules bind to a target protein and induce degradation of that protein through the recruitment of an E3 ligase complex. Using an ultra-high throughput cell-based screening platform, degraders of the bromodomain extra-terminal (BET) protein BRD4 were identified and optimized to yield a lead compound, PLX-3618. In this paper, we demonstrate that PLX-3618 elicited UPS-mediated selective degradation of BRD4, resulting in potent anti-tumor activity in vitro and in vivo. Characterization of the degradation mechanism identified DCAF11 as the E3 ligase required for PLX-3618-mediated degradation of BRD4. Protein-protein interaction studies verified a BRD4:PLX-3618:DCAF11 ternary complex, and mutational studies provided further insights into the DCAF11-mediated degradation mechanism. Collectively, these results demonstrate the discovery and characterization of a novel small molecule that selectively degrades BRD4 through the recruitment of the E3 substrate receptor, DCAF11, and promotes potent anti-tumor activity in vivo. [doi:10.25345/C5PN8XS4Q] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Targeted protein degradation ; Monovalent Degrader ; Bromodomain extra-terminal (BET) protein ; DCAF11

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Principal Investigators:
(in alphabetical order) 		Gregory S. Parker, Plexium, USA
Submitting User: alexcampos
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