化学
小分子
DNA
DNA修复
癌变
DNA损伤
分子生物学
费斯特共振能量转移
计算生物学
细胞生物学
基因
生物化学
生物
荧光
物理
量子力学
作者
Devan J. Shell,Caroline A. Foley,Qinhong Wang,Chelsea M. Smith,Shiva Krishna Reddy Guduru,Hong Zeng,Aiping Dong,Jacqueline Norris-Drouin,Matthew Axtman,P. Brian Hardy,Gaorav P. Gupta,Levon Halabelian,Stephen V. Frye,Lindsey I. James,Kenneth H. Pearce
标识
DOI:10.1021/acs.jmedchem.3c01192
摘要
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 chemical 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 ± 0.09 μM in a TR-FRET assay and Kd values of 0.85 ± 0.17 and 0.79 ± 0.52 μM in ITC and SPR, respectively. UNC8531 was cocrystallized 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 molecule 53BP1 antagonist that can aid further studies investigating the role of 53BP1 in DNA repair, gene editing, and oncogenesis.
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