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| Status |
Public on May 15, 2022 |
| Title |
Discovery of a dual PROTAC for degrading WDR5 and Ikaros oncoproteins as therapeutics [RNA-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
WD repeat domain 5 (WDR5), a chromatin regulator associated with MLL complex and MYC oncoproteins, was shown to be critical for oncogenesis in human cancers and represents an attractive drug target. Inhibitors for targeting protein-protein interaction interfaces (PPIs) within WDR5 were developed; however, they inhibited only a part of WDR5-mediated functional interactions, exerting rather limited antitumor effects. We report a cereblon (CRBN)-based proteolysis targeting chimera (PROTAC) of WDR5, MS40, which is capable of selectively degrading cellular WDR5 and well-established imide:CRBN targets such as Ikaros (IKZF1). MS40-induced WDR5 degradation caused disassociation of MLL complex off chromatin, resulting in a decrease of global H3K4me2. Transcriptomic profiling also revealed targets of both WDR5 and imide:CRBN to be repressed by MS40. In MLL-rearranged acute leukemias, which exhibit high IKZF1 expression and IKZF1 dependency, co-suppression of WDR5 and IKZF1/3 by MS40 is superior at suppressing tumor growth not only to WDR5 PPI inhibitors but also to a VHL-based WDR5 PROTAC, MS169, which selectively targets WDR5 only. Furthermore, MS40 suppressed growth of primary leukemia patient cells in vitro and patient-derived xenografts (PDX) in vivo. Collectively, we report the discovery of a dual WDR5 and Ikaros degrader as anti-cancer therapeutic.
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| Overall design |
Examination of transcriptome profiles using the MV4;11 cells treated with either DMSO, MS40 (a WDR5 and Ikaros degrader), MS40N1 (an E3-“dead” analog of MS40) or pomalidomide, or cells transduced with a WDR5-targeting hairpin (sh#47) or vector (shEV).
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| Contributor(s) |
Li D, Wang G |
| Citation(s) |
35525905 |
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| Submission date |
May 25, 2021 |
| Last update date |
Apr 26, 2024 |
| Contact name |
Gang Greg Wang |
| E-mail(s) |
greg_wang@med.unc.edu
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| Organization name |
University of North Carolina at chapel hill
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| Department |
UNC Lineberger Comprehensive Cancer Center; Department of Biochemistry and Biophysics
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| Lab |
gregwang lab
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| Street address |
405 West Drive
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| City |
Chapel Hill |
| State/province |
NORTH CAROLINA |
| ZIP/Postal code |
27599-7295 |
| Country |
USA |
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| Platforms (2) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE175548 |
Discovery of a dual PROTAC for degrading WDR5 and Ikaros oncoproteins as therapeutics |
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| Relations |
| BioProject |
PRJNA732786 |
| SRA |
SRP321449 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE175547_MV4_11_MS40_RNA-seq_processed.xlsx |
7.0 Mb |
(ftp)(http) |
XLSX |
| GSE175547_MV4_11_WDR5_sh_47_RNA-seq_processed.xlsx |
2.9 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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