Discovery of a dual PROTAC for degrading WDR5 and Ikaros oncoproteins as therapeutics [RNA-Seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA732786 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14651007.fastq.gz | Fastqsanger.gz | |||
| SRR14651008.fastq.gz | Fastqsanger.gz | |||
| SRR14651009.fastq.gz | Fastqsanger.gz | |||
| SRR14651010.fastq.gz | Fastqsanger.gz | |||
| SRR14651011.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description: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 the well-established IMiDs: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 revealed that gene targets of WDR5 and IMiDs:CRBN were both 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 matched 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.
2022-05-15 | GSE195729 | GEO
Project description: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.
2022-05-15 | GSE175547 | GEO
Project description: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.
2022-05-15 | GSE175544 | GEO
Project description:Discovery of a dual PROTAC for degrading WDR5 and Ikaros oncoproteins as therapeutics
| PRJNA732696 | ENA
Project description:Discovery of a dual PROTAC for degrading WDR5 and Ikaros oncoproteins as therapeutics [ChIP-Seq]
| PRJNA732785 | ENA
Project description:Discovery of a dual PROTAC for degrading WDR5 and Ikaros oncoproteins as therapeutics [GRO-Seq]
| PRJNA802030 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-05-15 | GSE175548 | GEO
Project description:WD repeat domain 5 (WDR5), an integral component of the MLL/KMT2A lysine methyltransferase complex, is critically involved in oncogenesis and represents an attractive onco-target. Inhibitors targeting protein-protein interactions (PPIs) between WDR5 and its binding partners, however, do not inhibit all of WDR5-mediated oncogenic functions and exert rather limited antitumor effects. Here, we report a cereblon (CRBN)-recruiting proteolysis targeting chimera (PROTAC) of WDR5, MS40, which selectively degrades WDR5 and the well-established neo-substrates of immunomodulatory drugs (IMiDs):CRBN, the Ikaros zinc finger (IKZF) transcription factors IKZF1 and IKZF3. MS40-induced WDR5 degradation caused disassociation of the MLL/KMT2A complex off chromatin, resulting in decreased H3K4me2. Transcriptomic profiling revealed that targets of both WDR5 and IMiDs:CRBN were significantly repressed by treatment of MS40. In MLL-rearranged leukemias, which exhibit IKZF1 high expression and dependency, co-suppression of WDR5 and Ikaros by MS40 is superior in suppressing oncogenesis to the WDR5 PPI inhibitor, to MS40's non-PROTAC analog controls (MS40N1 and MS40N2, which do not bind CRBN and WDR5, respectively), and to a matched VHL-based WDR5 PROTAC (MS169, which degrades WDR5 but not Ikaros). MS40 suppressed the growth of primary leukemia patient cells in vitro and patient-derived xenografts in vivo. Thus, dual degradation of WDR5 and Ikaros is a promising anti-cancer strategy.
| S-EPMC9189076 | biostudies-literature
Project description:Disease-causing aberrations of childhood cancers recurrently target the chromatin pathway genes leading to epigenetic dysregulation. For example, almost 100% of patients with synovial sarcoma (SS) carry an abnormal gene fusion termed SS18-SSX, which produces a disease-specific oncofusion protein that is incorporated into the SWI/SNF chromatin-remodeling complex and profoundly alters its functionalities. Thus, targeting epigenetic dependencies in childhood cancer holds great promise for improving current treatment of the affected patients. Leveraging on the cancer cell dependency dataset, medicinal chemistry tool compounds and genomic profiling approaches, we here show WDR5, a chromatin factor involved in the deposition of histone H3 lysine 4 (H3K4) methylation, to be an unexplored vulnerability of SS. Mechanistically, WDR5 and SS18-SSX associate with one another and colocalize significantly at the target oncogenes where WDR5 is essential for optimal chromatin binding of the SS18-SSX-containing chromatin modelers. Using the WDR5-targeted Proteolysis Targeting Chimera (PROTAC) compound, we further show that pharmacologic degradation of WDR5 in SS cells not only suppressed the SS18-SSX-related oncogenic gene-expression programs but additionally led to p53 activation and tumor cell senescence through downregulation of ribosomal proteins (RPs) and activation of nucleolar stress response. Importantly, the WDR5-targeted PROTAC significantly suppressed malignant growth of SS in vitro and in vivo. Taken together, we report WDR5 as a SS dependency and demonstrate the WDR5 PROTAC degrader to be a promising strategy for the treatment of SS.
2025-04-02 | GSE272211 | GEO
Project description:Disease-causing aberrations of childhood cancers recurrently target the chromatin pathway genes leading to epigenetic dysregulation. For example, almost 100% of patients with synovial sarcoma (SS) carry an abnormal gene fusion termed SS18-SSX, which produces a disease-specific oncofusion protein that is incorporated into the SWI/SNF chromatin-remodeling complex and profoundly alters its functionalities. Thus, targeting epigenetic dependencies in childhood cancer holds great promise for improving current treatment of the affected patients. Leveraging on the cancer cell dependency dataset, medicinal chemistry tool compounds and genomic profiling approaches, we here show WDR5, a chromatin factor involved in the deposition of histone H3 lysine 4 (H3K4) methylation, to be an unexplored vulnerability of SS. Mechanistically, WDR5 and SS18-SSX associate with one another and colocalize significantly at the target oncogenes where WDR5 is essential for optimal chromatin binding of the SS18-SSX-containing chromatin modelers. Using the WDR5-targeted Proteolysis Targeting Chimera (PROTAC) compound, we further show that pharmacologic degradation of WDR5 in SS cells not only suppressed the SS18-SSX-related oncogenic gene-expression programs but additionally led to p53 activation and tumor cell senescence through downregulation of ribosomal proteins (RPs) and activation of nucleolar stress response. Importantly, the WDR5-targeted PROTAC significantly suppressed malignant growth of SS in vitro and in vivo. Taken together, we report WDR5 as a SS dependency and demonstrate the WDR5 PROTAC degrader to be a promising strategy for the treatment of SS.
2025-04-02 | GSE287557 | GEO