Exploring the Ligandability of 53BP1 through Fragment-Based Approaches
53BP1 is a DNA damage response protein recruited to sites of double strand breaks through recognition of dimethylated lysine on histone 4 by its tandem Tudor domains. Like 53BP1, BRCA-1 plays a role in the regulation of DNA repair pathways, and BRCA-1 mutations have been strongly linked to breast and ovarian cancer. Interestingly, mice null for 53BP1 and BRCA-1 genes display minimal tumor formation, suggesting that the effects of deleterious BRCA-1 mutations could be prevented with potent 53BP1 small molecule antagonists. Herein, we describe a fragment screen that was used to identify compounds that bind to the 53BP1 Tudor domain and a chemoinformatic workflow to select near-neighbor analogues and establish structure activity relationships for these binders. The marked affinity improvements of the analogues over their parent fragments highlights the developability of these series and the utility of this approach in discovering novel hit compounds for 53BP1 and other methyl-lysine reader proteins.
Authors
- Caroline A. Foley (ORCID: https://orcid.org/0000-0003-4888-9948)
- Menachem J. Gunzburg (ORCID: https://orcid.org/0000-0001-7314-4636)
- Biswaranjan Mohanty (ORCID: https://orcid.org/0000-0002-6921-343X)
- M.J. Scanlon (ORCID: https://orcid.org/0000-0002-9230-7506)
- Juliana The
- B.C. Doak (ORCID: https://orcid.org/0000-0001-8422-675X)
- Beatrice Chiew (ORCID: https://orcid.org/0000-0001-5108-2729)
- Stephen J. Headey (ORCID: https://orcid.org/0000-0001-8015-7064)
- Lindsey Ingerman James (ORCID: https://orcid.org/0000-0002-6034-7116)
- Peter J. Brown (ORCID: https://orcid.org/0000-0002-8454-0367)
- Hong Zeng
- Stephanie H. Cholensky
- Jacqueline L. Norris‐Drouin (ORCID: https://orcid.org/0000-0003-1193-4514)
- Aiping Dong
Institutions
- University of Toronto (CA)
- Australian Regenerative Medicine Institute (AU)
- Monash University (AU)
- Monash Institute of Medical Research (AU)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-06-09
- DOI
- https://doi.org/10.1021/acsmedchemlett.5c00125
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Boehringer Ingelheim
- Pfizer
- Bayer
- Merck
- Novartis
- AbbVie
- Genome Canada
- Wellcome Trust
- Takeda Foundation
- Ontario Ministry of Economic Development and Innovation
- Canada Foundation for Innovation
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Innovative Medicines Initiative
- National Institute of General Medical Sciences
- Janssen Pharmaceuticals
- Eshelman Institute for Innovation, University of North Carolina at Chapel Hill