A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models
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ABSTRACT:
PROVIDER: PRJNA632759 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11789000.fastq.gz | Fastqsanger.gz | |||
| SRR11789001.fastq.gz | Fastqsanger.gz | |||
| SRR11789002.fastq.gz | Fastqsanger.gz | |||
| SRR11789003.fastq.gz | Fastqsanger.gz | |||
| SRR11789004.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models [ChIP-seq]
| PRJNA632756 | ENA
Project description:A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models[RNA-seq]
| PRJNA632769 | ENA
Project description:Biochemical interactions between WD40 repeat domain protein 5 (WDR5) and its various cellular partners such as Mixed Lineage Leukemia (MLL) and c-MYC are essential for sustaining oncogenesis in a range of human cancers. Thus, small molecules targeting WDR5 represent an attractive strategy for anti-cancer interventions. However, currently available inhibitors designed to interfere with WDR5 binding to a specific partner (such as OICR-9429 that blocks WDR5-MLL interaction) show a promising but rather partial therapeutic effect, presumably due to incomplete blockade of WDR5 functionality and interactions with various partners. Here, we report the first-in-class, OICR-9429-based proteolysis targeting chimeras (PROTACs) of WDR5, including a prototypic compound MS33 and a further optimized MS67, that achieve specific and efficient depletion of WDR5 in cancer cells. Such an effect is not seen with OICR-9429 or MS33/67 analogs that are incapable of E3 ligand conjugation. Medicinal chemistry, structural and cellular characterizations demonstrate that MS33 and MS67 bind both WDR5 and an E3 ligand VHL tightly, with MS67 showing a unique cooperative binding, an event that subsequently induces degradation of WDR5 through a VHL- and proteasome-dependent mechanism. Global proteomics profiling shows a highly specific effect of MS67 on WDR5. Genomics analysis further demonstrates that, relative to non-degrading inhibitors, MS67 is far more potent in suppressing overall transcription of WDR5-regulated genes crucially involved in oncogenesis and in reducing global H3K4 methylation, an enzymatic product of MLL/WDR5 complex. Importantly, using a panel of human MLL-rearranged acute myeloid leukemia (MLL-r AML) and pancreatic ductal adenocarcinoma (PDAC) cells, we found that, relative to non-degrading inhibitor controls, MS67 displays a superior anti-growth effect. MS67 also demonstrates optimal PK/PD properties in vivo and treatment with MS67 significantly suppressed tumorigenesis of MLL-r AML in tumor xenografted animal models. Together, this study reports the first-in-class PROTACs of WDR5 and demonstrates its advantageous efficacies in the treatment of WDR5-dependent cancers.
2021-09-29 | GSE150552 | GEO
Project description:Biochemical interactions between WD40 repeat domain protein 5 (WDR5) and its various cellular partners such as Mixed Lineage Leukemia (MLL) and c-MYC are essential for sustaining oncogenesis in a range of human cancers. Thus, small molecules targeting WDR5 represent an attractive strategy for anti-cancer interventions. However, currently available inhibitors designed to interfere with WDR5 binding to a specific partner (such as OICR-9429 that blocks WDR5-MLL interaction) show a promising but rather partial therapeutic effect, presumably due to incomplete blockade of WDR5 functionality and interactions with various partners. Here, we report the first-in-class, OICR-9429-based proteolysis targeting chimeras (PROTACs) of WDR5, including a prototypic compound MS33 and a further optimized MS67, that achieve specific and efficient depletion of WDR5 in cancer cells. Such an effect is not seen with OICR-9429 or MS33/67 analogs that are incapable of E3 ligand conjugation. Medicinal chemistry, structural and cellular characterizations demonstrate that MS33 and MS67 bind both WDR5 and an E3 ligand VHL tightly, with MS67 showing a unique cooperative binding, an event that subsequently induces degradation of WDR5 through a VHL- and proteasome-dependent mechanism. Global proteomics profiling shows a highly specific effect of MS67 on WDR5. Genomics analysis further demonstrates that, relative to non-degrading inhibitors, MS67 is far more potent in suppressing overall transcription of WDR5-regulated genes crucially involved in oncogenesis and in reducing global H3K4 methylation, an enzymatic product of MLL/WDR5 complex. Importantly, using a panel of human MLL-rearranged acute myeloid leukemia (MLL-r AML) and pancreatic ductal adenocarcinoma (PDAC) cells, we found that, relative to non-degrading inhibitor controls, MS67 displays a superior anti-growth effect. MS67 also demonstrates optimal PK/PD properties in vivo and treatment with MS67 significantly suppressed tumorigenesis of MLL-r AML in tumor xenografted animal models. Together, this study reports the first-in-class PROTACs of WDR5 and demonstrates its advantageous efficacies in the treatment of WDR5-dependent cancers.
2021-09-29 | GSE150554 | GEO
Project description:Interactions between WD40 repeat domain protein 5 (WDR5) and its various partners such as mixed lineage leukemia (MLL) and c-MYC are essential for sustaining oncogenesis in human cancers. However, inhibitors that block protein-protein interactions (PPIs) between WDR5 and its binding partners exhibit modest cancer cell killing effects and lack in vivo efficacy. Here, we present pharmacological degradation of WDR5 as a promising therapeutic strategy for treating WDR5-dependent tumors and report two high-resolution crystal structures of WDR5-degrader-E3 ligase ternary complexes. We identified an effective WDR5 degrader via structure-based design and demonstrated its in vitro and in vivo antitumor activities. On the basis of the crystal structure of an initial WDR5 degrader in complex with WDR5 and the E3 ligase von Hippel–Lindau (VHL), we designed a WDR5 degrader, MS67, and demonstrated the high cooperativity of MS67 binding to WDR5 and VHL by another ternary complex structure and biophysical characterization. MS67 potently and selectively depleted WDR5 and was more effective than WDR5 PPI inhibitors in suppressing transcription of WDR5-regulated genes, decreasing the chromatin-bound fraction of MLL complex components and c-MYC, and inhibiting the proliferation of cancer cells. In addition, MS67 suppressed malignant growth of MLL-rearranged acute myeloid leukemia patient cells in vitro and in vivo and was well tolerated in vivo. Collectively, our results demonstrate that structure-based design can be an effective strategy to identify highly active degraders and suggest that pharmacological degradation of WDR5 might be a promising treatment for WDR5-dependent cancers.
| S-EPMC8500670 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-09-29 | GSE150555 | GEO
Project description:HDAC3 and HDAC8 are members of class I deacetylases involved in several biological mechanisms and represent a highly sought-after therapeutic target for drug development. It is historically challenging to develop selective deacetylase inhibitors due to their conserved catalytic domains. HDAC3 also has deacetylase-independent activity, which cannot be blocked by conventional enzymatic inhibitors. Recent advance in proteolysis-targeting chimeras (PROTACs) provides an opportunity to eliminate the whole protein selectively, abolishing both enzymatic and scaffolding function. Here, we report a novel HDAC3/8 dual degrader YX968 that induces highly potent, rapid, and selective degradation of both HDAC3 and HDAC8 without trigging pan-HDAC inhibitory effects. Unbiased quantitative proteomics experiments further confirmed its high selectivity. This dual-specific degrader specifically ablates cellular pathways attributed to HDAC3 and HDAC8 and exhibits high potency in killing cancer cells. YX968 represents a new probe for dissecting the complex biological functions of HDAC3 and HDAC8.
2023-07-18 | GSE211758 | GEO
Project description:Active gene transcription requires accessible chromatin. Post-translational modifications of histone proteins modulate accessibility to target genes, a process that is controlled by multiple chromatin modifying enzymes, remodelers and epigenetic reader proteins. Histone H3K4 methylation serves as hallmark of actively transcribed genes and is introduced by histone methyltransferases (HMTs). For proper function of HMT activity, several adaptor proteins are required. One of these proteins is the WD-repeat containing protein 5 (WDR5) that acts as scaffolding component in HMT complexes and that has been associated with controlling transcription factors including MYC and long non-coding RNAs. The wide influence of dysfunctional HMTs complexes and the typically upregulated MYC levels in diverse tumor types has made WDR5 an attractive cancer drug target. Indeed, protein-protein interface inhibitors for two protein interaction interfaces on WDR5 have been developed. While such compounds only inhibit a subset of WDR5 interactions, chemically induced proteasomal degradation of WDR5 might be an elegant way to target all oncogenic function. In this study, we present the design, synthesis and evaluation of two diverse WDR5 degrader series based on two WIN site binding scaffolds. We show that linker nature and length are essential for successful degradation and strongly influences the degradation rate. In the presented datasets, we determined the intracellular degradation specificity of the WDR5 PROTACs (8g, 6, 17b, 14). We therefore treated MV4-11 cells with 8g and 17b, the corresponding ligands 6 and 14, or DMSO and quantified the induced degradation using a label free approach.
2022-01-27 | PXD025257 | Pride
Project description:WD repeat domain 5 (WDR5) plays an important role in various biological functions through the epigenetic regulation of gene transcription. However, the oncogenic effect of WDR5 in leukemia remains largely unknown. Here, we found WDR5 expression is increased in leukemia patients. High expression of WDR5 is associated with high risk leukemia; Patients with WDR5 and MLL1 high expression have poor complete remission rate. We further identified the global genomic binding of WDR5 in leukemic cells and found the genomic co-localization of WDR5 binding with H3K4me3 enrichment. Moreover, WDR5 knockdown by shRNA suppresses cell proliferation, induces apoptosis, inhibits the expression of WDR5 targets, and blocks the H3K4me3 enrichment on the promoter of its targets. We also observed the positive correlation of WDR5 expression with these targets in the cohort study of leukemia patients. Our data reveal that WDR5 may have oncogenic effect and WDR5-mediated H3K4 methylation plays an important role in leukemogenesis.
2016-12-30 | GSE72864 | GEO