Fragment-Based Screening of NSD2-PWWP1 Identifies Novel Covalent Allosteric Ligands That Diminish Methyllysine and DNA Binding Abilities of NSD2
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 <b>13</b> and <b>16</b> 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.
Authors
- Yanxi Li (ORCID: https://orcid.org/0009-0001-8212-102X)
- Jinrong Min (ORCID: https://orcid.org/0000-0001-5210-3130)
- Jian Wan (ORCID: https://orcid.org/0000-0003-4172-1392)
- Yunyuan Huang (ORCID: https://orcid.org/0000-0003-1857-9498)
- Yanliang Ren (ORCID: https://orcid.org/0000-0001-8565-2152)
- Yuxuan Li (ORCID: https://orcid.org/0000-0002-5145-8607)
- Xin Chen (ORCID: https://orcid.org/0000-0003-2931-2158)
- Qian Wang (ORCID: https://orcid.org/0000-0002-2499-1553)
- Siying Liu (ORCID: https://orcid.org/0000-0003-3533-8768)
- Huiling Wang (ORCID: https://orcid.org/0000-0001-7897-505X)
- Jun Ma (ORCID: https://orcid.org/0000-0003-2216-5714)
- Zeyue Huang
- Zhuo Chen (ORCID: https://orcid.org/0000-0001-6453-0447)
Institutions
- Ministry of Education of the People's Republic of China (CN)
- Jinan University (CN)
- Central China Normal University (CN)
- Laboratoire de Chémo-biologie synthétique et thérapeutique (FR)
- Ministry of Education (ME)
- Shanghai Pesticide Research Institute (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-11-20
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01902
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.00