Gavin W. Collie*, Bryony Ackroyd, Catriona Corbishley, Daniel H. O’Donovan, Alex Edwards, Andrea Gohlke, Xiaoxiao Guo, Bethan Howells, Yuliang Li, Andrew Madin, Alexander G. Milbradt, Emma L. Rivers*,Sandeep K. Talapatra, Elizabeth Underwood, and Alice Webb

ACS Med. Chem. Lett. 

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.