UNC-9512

Methyl-lysine reader p53 binding protein 1 (53BP1) is a central mediator of DNA break repair and is associated with various human diseases, including cancer.Thus, high-quality 53BP1 chem. probes can aid in further understanding the role of 53BP1 in genome repair pathways.Herein, we utilized focused DNA-encoded library screening to identify the novel hit compound UNC8531, which binds the 53BP1 tandem Tudor domain (TTD) with an IC50 of 0.47 ± 0.09μM in a TR-FRET assay and Kd values of 0.85 ± 0.17 and 0.79 ± 0.52μM in ITC and SPR, resp.UNC8531 was cocrystd. with the 53BP1 TTD to guide further optimization efforts, leading to UNC9512.NanoBRET and 53BP1-dependent foci formation experiments confirmed cellular target engagement.These results show that UNC9512 is a best-in-class small mol. 53BP1 antagonist that can aid further studies investigating the role of 53BP1 in DNA repair, gene editing, and oncogenesis.