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| Status |
Public on Aug 31, 2021 |
| Title |
An NSD3-targeting PROTAC (Proteolysis Targeting Chimeric) suppresses the NSD3 and cMyc oncogenic nodes in cancer cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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, agent that can effectively suppress the NSD3-mediated oncogenic actions is currently lacking. Here, we report an NSD3-targeting proteolysis targeting chimera (PROTAC), termed MS9715, which achieves effective and specific depletion of NSD3 and interacting partners (including cMyc) in tumor cells. We show that MS9715-induced NSD3 degradation relies on BI-9321, an antagonist module binding the PWWP1 domain of NSD3, and VHL, which is chemically conjugated to BI-9321 via a linker and a VHL ligand. Importantly, compared to BI-9321, a recently disclosed NSD3 antagonist, MS9715 is more potent in suppressing growth of the NSD3-dependent hematological cancer including models of MLL-rearranged acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL) and multiple myeloma (MM), and uniquely mediates simultaneous depletion of cellular NSD3 and cMyc. Transcriptome profiling further demonstrates effective actions of MS9715 but not BI-9321 in suppressing both the NSD3- and cMyc-mediated gene-expression programs, a phenomenon reminiscent of the CRISPR/cas9-mediated knockout (KO) of NSD3. Together, this study reports a first-in-class NSD3 degrader suitable for co-suppressing NSD3- and cMyc-related oncogenic nodes in cancer, suggesting a novel therapeutic strategy,
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| Overall design |
Examination of transcriptome profiles in the EOL-1 cells post-treatment with 2.5 μM of either DMSO, BI-9321 (an NSD3 PWWP1 binding inhibitor), MS9715 (a BI-9321- and VHL-dependent PROTAC degrader of NSD3) or MS9715N (an MS9715-related analog compound incapable of binding to VHL E3 ligase).
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| Contributor(s) |
Xu C, Wang GG |
| Citation(s) |
34469831 |
| Submission date |
Sep 21, 2020 |
| Last update date |
Nov 30, 2021 |
| Contact name |
Chenxi Xu |
| E-mail(s) |
xuchenxi@email.unc.edu
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| Phone |
9199034127
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| Organization name |
University of North Carolina at Chapel Hill
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| Department |
Lineberger Comprehensive Cancer Center
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| Lab |
Greg Wang lab
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| Street address |
450 West Drive, CB 7295, UNC cancer center, room 31-331 Chapel Hill, NC
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| City |
Chapel Hill |
| State/province |
North Carolina |
| ZIP/Postal code |
27599 |
| Country |
USA |
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| Platforms (1) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA664766 |
| SRA |
SRP284263 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE158296_Combined_DESeq_EOL1_BI_9321_vs_DMSO.xls.gz |
586.3 Kb |
(ftp)(http) |
XLS |
| GSE158296_Combined_DESeq_EOL1_MS9715N_vs_DMSO.xls.gz |
585.4 Kb |
(ftp)(http) |
XLS |
| GSE158296_Combined_DESeq_EOL1_MS9715_vs_DMSO.xls.gz |
620.0 Kb |
(ftp)(http) |
XLS |
| GSE158296_Combined_DESeq_EOL1_MS9715_vs_MS9715N.xls.gz |
598.0 Kb |
(ftp)(http) |
XLS |
| GSE158296_Combined_DESeq_EOL1_sgNSD3_vs_sgEV.xls.gz |
593.7 Kb |
(ftp)(http) |
XLS |
| GSE158296_Matrix_countTable_DESeq_EOL1_20200918.xlsx |
4.6 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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