2. Academic Validation
  3. Discovery of a 53BP1 Small Molecule Antagonist Using a Focused DNA-Encoded Library Screen

Discovery of a 53BP1 Small Molecule Antagonist Using a Focused DNA-Encoded Library Screen

  • J Med Chem. 2023 Oct 2. doi: 10.1021/acs.jmedchem.3c01192.
Devan J Shell 1,  Caroline A Foley 1,  Qinhong Wang 2,  Chelsea M Smith 3,  Shiva K R Guduru 1,  Hong Zeng 4,  Aiping Dong 4,  Jacqueline L Norris-Drouin 1,  Matthew Axtman 1,  P Brian Hardy 1,  Gaorav Gupta 2 3,  Levon Halabelian 4 5,  Stephen V Frye 1 2,  Lindsey I James 1 2,  Kenneth H Pearce 1 2
Affiliations

Affiliations

  • 1 UNC Eshelman School of Pharmacy, Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 2 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 3 Lineberger Comprehensive Cancer Center, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 4 Structural Genomics Consortium, University of Toronto, Ontario M5S 1A1, Canada.
  • 5 Department of Pharmacology and Toxicology, University of Toronto, Ontario M5S 1A1, Canada.
PMID: 37782247 DOI: 10.1021/acs.jmedchem.3c01192
Abstract

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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