Structural and Molecular Insight into the PWWP1 Domain of NSD2 from the Discovery of Novel Binders Via DNA-Encoded Library Screening

  • ACS Med Chem Lett. 2025 Aug 25;16(9):1703-1708. doi: 10.1021/acsmedchemlett.5c00396.
Gavin W Collie  1 ,  Bryony Ackroyd  1 ,  Catriona Corbishley  1 ,  Daniel H O'Donovan  2 ,  Alex Edwards  1 ,  Andrea Gohlke  1 ,  Xiaoxiao Guo  1 ,  Bethan Howells  1 ,  Yuliang Li  3 ,  Andrew Madin  1 ,  Alexander G Milbradt  1 ,  Emma L Rivers  1 ,  Sandeep K Talapatra  1 ,  Elizabeth Underwood  1 ,  Alice Webb  1
Affiliations
  • 1. Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 2. Oncology R&D , AstraZeneca, Cambridge CB2 0AA, U.K.
  • 3. Pharmaron Beijing Co., Ltd., Beijing 100176, P.R. China.
PMID: 40959233 DOI: 10.1021/acsmedchemlett.5c00396
Abstract

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.

Keywords
DEL; NSD2; PWWP1; drug discovery; encoded library.
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