2. Academic Validation
  3. Fragment-Based Screening of NSD2-PWWP1 Identifies Novel Covalent Allosteric Ligands That Diminish Methyllysine and DNA Binding Abilities of NSD2

Fragment-Based Screening of NSD2-PWWP1 Identifies Novel Covalent Allosteric Ligands That Diminish Methyllysine and DNA Binding Abilities of NSD2

  • J Med Chem. 2025 Dec 11;68(23):24953-24967. doi: 10.1021/acs.jmedchem.5c01902.
Yunyuan Huang 1,  Yanxi Li 1,  Xin Chen 2,  Huiling Wang 3,  Qian Wang 1,  Siying Liu 1,  Yigui Li 2,  Zhuo Chen 1,  Jun Ma 1,  Zeyue Huang 3,  Jian Wan 3,  Yanliang Ren 3,  Jinrong Min 1
Affiliations

Affiliations

  • 1 Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, China.
  • 2 State Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Pharmacy, Jinan University, Guangzhou 510632, China.
  • 3 State Key Laboratory of Green Pesticide, Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Hubei International Scientific and Technological Cooperation Base of Pesticide and Green Synthesis, College of Chemistry, Central China Normal University, Wuhan 430079, China.
PMID: 41264880 DOI: 10.1021/acs.jmedchem.5c01902
Abstract

The PWWP1 domain of NSD2 recognizes both H3K36me2/3 and DNA, a function critical for its subcellular localization and oncogenic activity, making it a promising therapeutic target. In this study, through fragment library screening and structure-activity relationship studies, we identified compounds that covalently bind to the C294 residue of NSD2-PWWP1. Structural and biochemical analyses demonstrated that compounds 13 and 16 competitively block NSD2-PWWP1's recognition of both H3K36me2 and DNA, thereby impairing its nucleosome-binding ability. This study uncovers a novel allosteric regulatory mechanism and provides a structural framework for the development of more effective Cancer therapeutics targeting NSD2-PWWP1.

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