Biological and Medicinal Chemistry

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

Authors

  • Na Li Shanghai Institute of Materia Medica ,
  • Hong Yang Shanghai Institute of Materia Medica, CAS ,
  • Ke Liu Shanghai Synchrotron Radiation Facility, Shanghai Advanced Research Institute ,
  • Liwei Zhou Shanghai Institute of Materia Medica, CAS ,
  • Yuting Huang Shanghai Institute of Materia Medica ,
  • Danyan Cao Shanghai Institute of Materia Medica ,
  • Yanlian Li Shanghai Institute of Materia Medica ,
  • Yaoliang Sun Shanghai Institute of Materia Medica ,
  • Aisong Yu Shanghai Institute of Materia Medica ,
  • Zhiyan Du Shanghai Institute of Materia Medica ,
  • Feng Yu Shanghai Synchrotron Radiation Facility ,
  • Ying Zhang Shanghai Institute of Materia Medica ,
  • Bingyang Wang Shanghai Institute of Materia Medica ,
  • Meiyu Geng Shanghai Institute of Materia Medica, CAS ,
  • Jian Li Gannan Medical University ,
  • Shilin Xu Shanghai Institute of Materia Medica,CAS ,
  • Bing Xiong Shanghai Institute of Materia Medica, CAS ,
  • Xun Huang Shanghai Institute of Materia Medica,CAS ,
  • Tongchao Liu Shanghai Institute of Materia Medica,CAS

Abstract

Overexpression, point mutations or translocations of protein lysine methyltransferase NSD2 was occurred in many types of cancer cells. Therefore, it was recognized as onco-protein and considered as a promising anticancer drug target. NSD2 consists of 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 a potent inhibitor 38, which has the high selectivity towards 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.

Version notes

update the main text by including the RNA-seq data. Update the authors

Content

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