Targeting METTL3 protein by PROTAC: A Novel Therapeutic Approach for Acute Myeloid Leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1141488 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR30027206_1.fastq.gz | Fastqsanger.gz | |||
| SRR30027206_2.fastq.gz | Fastqsanger.gz | |||
| SRR30027208_1.fastq.gz | Fastqsanger.gz | |||
| SRR30027208_2.fastq.gz | Fastqsanger.gz |
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Project description:MDM2 inhibitor remarkably induced biomineralization in hDPSCs but it remained the problem that p53 activation is insufficient due to MDM2-p53 autoregulatory feedback loop. To overcome the limitation of the MDM2 inhibitors, we applied proteolysis targeting chimera (PROTAC), a technology that degrades a protein of interest (POI) by intracellular ubiquitin-proteasome system. Hence, we propose a strategy to induce hard tissue regeneration by MDM2-targeting PROTAC technology. We selected Nutlin-3 of POI ligand among various MDM2 inhibitors based on the screening process, and the selected CRBN of E3 ligase ligand. The MDM2-PROTAC synthesis platform was designed by each ligand combination. By performing the degradation test for selected compounds, we evaluated the characteristics of the developed MDM2 PROTAC such as the maximal degradation concentration (DCmax), the half of maximal degradation concentration (DC50), and half-lifetime. To investigate gene expression profiling of MDM2-targeting small molecules, we conducted RNA-sequencing under MDM2 PROTAC and Nutlin-3 (POI ligand) treated conditions. We not only confirmed a robust effect on biomineralization by MDM2-targeting small molecules but also demonstrated the potent osteogenic differentiation ability of MDM2 PROTAC when compared to an MDM2 inhibitor. MDM2-PROTAC significantly increased mRNA levels of osteogenic differentiation marker genes. Also, the significant bone generation effect of MDM2 PROTAC was validated in an ovariectomy (OVX)-induced osteoporosis animal model. Through these results, it is expected that a new therapeutic modality for hard tissue regeneration will be possible, and the application range of the PROTAC system can be expanded.
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Project description:The role of signal transducer and activator of transcription protein 3 (STAT3) in AKI remains controversial. Our study demonstrated an upregulation of total STAT3 protein in AKI mouse models induced by cecal ligation and puncture (CLP) or ischemia-reperfusion (I/R), correlating with patient biopsy results. This increase may be attributed to histone H3K27 acetylation. STAT3 knockout in renal tubular epithelial cells significantly reduced AKI injury and inflammation in mice. Mechanistically, STAT3 induces the transcription of tripartite motif-containing protein 21 (TRIM21), triggering a cascade that activates gasdermin D (GSDMD), resulting in pyroptosis. Administration of the novel proteolysis-targeting chimera (PROTAC) compound E034, which selectively targets STAT3 for ubiquitination and degradation, significantly alleviated renal injury in a low-dose, single-dose regimen, underscoring its substantial therapeutic potential with infrequent dosing requirements. In the context of renal injury, PROTAC emerges as a promising modality by specifically targeting the STAT3/TRIM21/GSDMD axis, which our study has identified as a potential therapeutic target, thereby potentially endowing novel and clinically significant therapeutic strategies.
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Project description:The role of signal transducer and activator of transcription protein 3 (STAT3) in AKI remains controversial. Our study demonstrated an upregulation of total STAT3 protein in AKI mouse models induced by cecal ligation and puncture (CLP) or ischemia-reperfusion (I/R), correlating with patient biopsy results. This increase may be attributed to histone H3K27 acetylation. STAT3 knockout in renal tubular epithelial cells significantly reduced AKI injury and inflammation in mice. Mechanistically, STAT3 induces the transcription of tripartite motif-containing protein 21 (TRIM21), triggering a cascade that activates gasdermin D (GSDMD), resulting in pyroptosis. Administration of the novel proteolysis-targeting chimera (PROTAC) compound E034, which selectively targets STAT3 for ubiquitination and degradation, significantly alleviated renal injury in a low-dose, single-dose regimen, underscoring its substantial therapeutic potential with infrequent dosing requirements. In the context of renal injury, PROTAC emerges as a promising modality by specifically targeting the STAT3/TRIM21/GSDMD axis, which our study has identified as a potential therapeutic target, thereby potentially endowing novel and clinically significant therapeutic strategies.
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