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Design, Preparation, and Screening of BRPF1b Degraders

Targeted protein degradation (TPD) is revolutionizing small molecule drug discovery by directing protein degradation rather than inhibition, making it a potent strategy against "undruggable" targets. PROteolysis TArgeting Chimeras (PROTACs) and molecular glues are the two main types of degraders and they facilitate the interaction between an E3 ligase and the protein of interest to initiate degradation. The Bromodomain and PHD Finger-containing (BRPF) family, including BRPF1 and BRPF2/BRD1, are key epigenetic proteins involved in cancer, inflammation, and neurological disorders. BRPF1 is a promising therapeutic target for acute myeloid leukemia and hepatocellular carcinoma. In this study, we have developed a workflow for designing and synthesizing BRPF1b-targeted degraders. These degraders show favorable ADME parameters, and we have confirmed that two of these degraders form binary complexes resulting in reduced viability and BRPF1b degradation in THP-1 cells.

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