2. Academic Validation
  3. Structure-Based Discovery of a Series of NSD2-PWWP1 Inhibitors

Structure-Based Discovery of a Series of NSD2-PWWP1 Inhibitors

  • J Med Chem. 2022 Jul 14;65(13):9459-9477. doi: 10.1021/acs.jmedchem.2c00709.
Na Li 1 2,  Hong Yang 3,  Ke Liu 4,  Liwei Zhou 1,  Yuting Huang 3,  Danyan Cao 1,  Yanlian Li 1,  Yaoliang Sun 5,  Aisong Yu 3,  Zhiyan Du 1,  Feng Yu 4,  Ying Zhang 3,  Bingyang Wang 5,  Meiyu Geng 3 6,  Jian Li 7,  Bing Xiong 1 2,  Shilin Xu 5,  Xun Huang 3 6,  Tongchao Liu 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
  • 2 University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, P. R. China.
  • 3 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
  • 4 Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute, Chinese Academy of Sciences, 239 Zhangheng Road, Shanghai 201210, P. R. China.
  • 5 Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, #555 ZuChong Zhi Road, Shanghai 201203, P. R. China.
  • 6 Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, P. R. China.
  • 7 College of Pharmaceutical Sciences, Gannan Medical University, Ganzhou 341000, P. R. China.
PMID: 35704853 DOI: 10.1021/acs.jmedchem.2c00709
Abstract

Overexpression, point mutations, or translocations of protein lysine methyltransferase NSD2 occur in many types of Cancer cells. Therefore, it was recognized as onco-protein and considered as a promising Anticancer drug target. NSD2 consists of multiple domains including a SET catalytic domain and two PWWP domains binding to methylated histone proteins. Here, we reported our efforts to develop a series of NSD2-PWWP1 inhibitors, and further structure-based optimization resulted in a potent inhibitor 38, which has high selectivity toward the NSD2-PWWP1 domain. The detailed biological evaluation revealed that compound 38 can bind to NSD2-PWWP1 and then affect the expression of genes regulated by NSD2. The current discovery will provide a useful chemical probe to the future research in understanding the specific regulation mode of NSD2 by PWWP1 recognition and pave the way to develop potential drugs targeting NSD2 protein.

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