期刊
CELL CHEMICAL BIOLOGY
卷 29, 期 3, 页码 386-+出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2021.08.004
关键词
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资金
- US National Institutes of Health [R01GM122749, P30CA196521, R01CA211336, R01CA215284, R24GM137786, P20GM121293, R01CA236209, P20GM103429]
- NIH/Office of the Director Grant [S10OD018445]
- Icahn School of Medicine at Mount Sinai
- Gabrielle's Angel Foundation for Cancer Research
- When Everyone Survives (WES) Leukemia Research Foundation
- UNC Lineberger Cancer Center UCRF Stimulus Initiative Grants
- National Institutes of Health SIG grant [1S10OD025132-01A1]
- UNC Lineberger Comprehensive Cancer Center Core Support Grant [P30CA016086]
This study reports a proteolysis targeting chimera (PROTAC) that specifically targets Nuclear receptor binding SET domain protein 3 (NSD3) and its associated cMyc node in tumor cells. The PROTAC effectively suppressed the growth of NSD3-dependent hematological cancer cells and resulted in similar gene expression changes as the knockout of NSD3 by CRISPR-Cas9.
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.
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