Structural and Molecular Insight into the PWWP1 Domain of NSD2 from the Discovery of Novel Binders Via DNA-Encoded Library Screening
NSD2 is a key epigenetic regulator and has received considerable attention as a drug target due to its well-documented role in tumorigenesis. We report here a DNA-encoded library screen targeting the PWWP1 domain of NSD2 from which we discovered novel, potent, and selective binders. Furthermore, these compounds were used to develop a novel crystal system, increasing our understanding of the folding of this domain. Together, these results provide a solid molecular and structural basis for the further study of the PWWP1 domain of NSD2 as a cancer drug target.
Authors
- Andrew Madin
- Emma L. Rivers
- Alexander G. Milbradt
- Sandeep K. Talapatra (ORCID: https://orcid.org/0000-0002-5474-0114)
- A. Dinsmoor Webb (ORCID: https://orcid.org/0009-0008-7020-8233)
- Gavin W. Collie (ORCID: https://orcid.org/0000-0002-0406-922X)
- Cathy Corbishley
- Bryony Ackroyd
- Daniel H. O’Donovan (ORCID: https://orcid.org/0000-0002-8400-2198)
- Andrea Gohlke (ORCID: https://orcid.org/0000-0002-5447-5453)
- Yuliang Li (ORCID: https://orcid.org/0000-0001-8117-4317)
- Xiaoxiao Guo
- Elizabeth Underwood
- Alex Edwards (ORCID: https://orcid.org/0009-0000-6518-5374)
- Bethan Howells
Institutions
- AstraZeneca (United Kingdom) (GB)
- Pharmaron (United Kingdom) (GB)
- AstraZeneca (Brazil) (BR)
- AstraZeneca (Poland) (PL)
- AstraZeneca (Germany) (DE)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-08-25
- DOI
- https://doi.org/10.1021/acsmedchemlett.5c00396
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.00