A NSD3-targeted PROTAC suppresses NSD3 and cMyc oncogenic nodes in cancer cells

Chenxi Xu, Fanye Meng, Kwang Su Park, Aaron J. Storey, Weida Gong, Yi Hsuan Tsai, Elisa Gibson, Stephanie D. Byrum, Dongxu Li, Rick D. Edmondson, Samuel G. Mackintosh, Masoud Vedadi, Ling Cai, Alan J. Tackett, H. Ümit Kaniskan, Jian Jin, Gang Greg Wang

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Nuclear receptor binding SET domain protein 3 (NSD3), a gene located within the 8p11-p12 amplicon frequently detected in human cancers, encodes a chromatin modulator and an attractive onco-target. However, agents that effectively suppress NSD3-mediated oncogenic actions are currently lacking. We report the NSD3-targeting proteolysis targeting chimera (PROTAC), MS9715, which achieves effective and specific targeting of NSD3 and associated cMyc node in tumor cells. MS9715 is designed by linking BI-9321, a NSD3 antagonist, which binds NSD3’s PWWP1 domain, with an E3 ligase VHL ligand. Importantly, MS9715, but not BI-9321, effectively suppresses growth of NSD3-dependent hematological cancer cells. Transcriptomic profiling demonstrates that MS9715, but not BI-9321, effectively suppresses NSD3-and cMyc-associated gene expression programs, resembling effects of the CRISPR-Cas9-mediated knockout of NSD3. Collectively, these results suggest that pharmacological degradation of NSD3 as an attractive therapeutic strategy, which co-suppresses NSD3- and cMyc-related oncogenic nodes, is superior to blocking the PWWP1 domain of NSD3.

Original languageEnglish
Pages (from-to)386-397.e9
JournalCell Chemical Biology
Volume29
Issue number3
DOIs
StatePublished - 17 Mar 2022

Keywords

  • NSD3
  • PROTAC
  • cMyc
  • cancer
  • chromatin
  • degrader
  • epigenetics
  • histone
  • ubiquitylation

Fingerprint

Dive into the research topics of 'A NSD3-targeted PROTAC suppresses NSD3 and cMyc oncogenic nodes in cancer cells'. Together they form a unique fingerprint.

Cite this