AI Article Synopsis
- NSD3 is a gene linked to various human cancers and encodes a chromatin modulator that represents a potential target for cancer therapy, but current treatments to inhibit its oncogenic effects are lacking.
- Researchers have developed a new compound called MS9715, a proteolysis targeting chimera (PROTAC), which effectively and specifically targets NSD3 and its connection to cMyc in tumor cells.
- MS9715 demonstrates superior cancer suppression compared to the NSD3 antagonist BI-9321, as it reduces NSD3 and cMyc-related gene expression, suggesting that targeting NSD3 for degradation could be a promising therapeutic approach in treating NSD3-dependent hematological cancers.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8882712 | PMC |
| http://dx.doi.org/10.1016/j.chembiol.2021.08.004 | DOI Listing |
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