Development of a First-in-Class DNMT1/HDAC Inhibitor with Improved Therapeutic Potential and Potentiated Antitumor Immunity
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ABSTRACT:
PROVIDER: PRJNA1103160 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28770800_1.fastq.gz | Fastqsanger.gz | |||
| SRR28770800_2.fastq.gz | Fastqsanger.gz | |||
| SRR28770801_1.fastq.gz | Fastqsanger.gz | |||
| SRR28770801_2.fastq.gz | Fastqsanger.gz | |||
| SRR28770802_1.fastq.gz | Fastqsanger.gz |
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Project description:Epigenetic therapies have emerged as an up-and-coming strategy avenue for treating cancer treatmentmalignancies. In this study, a series of DNMT1/HDAC dual inhibitors were obtained by merging pharmacophores. Among them, compound (R)-23a stood out due to balanced inhibition of DNMT1 and HDAC, along with excellent anti-tumor effects in vitro by stimulating both histone acetylation and DNA methylation. Notably, treatment with compound (R)-23a resulted in a significant anti-tumor effect (TGI = 98%) on MV-4-11 xenograft models, surpassing that achieved with combination therapy. Additionally, compound (R)-23a demonstrated the ability to dramatically reduce tumor volume or even induce tumor regression in MC38 murine colon cancer models. However, this effect was compromised under conditions of immune deficiency. In conclusion, the novel DNMT1/HDAC dual inhibitor (R)-23a holds promise for the development of multiple-target anti-AML agents and tumor immunotherapy.
2024-09-10 | GSE264565 | GEO
Project description:The β-thalassemia is a recessively inherited disease affecting millions around the world. Pharmacological induction of fetal hemoglobin (HbF) is an effective therapeutic strategy for the management of β-thalassemia. DNA methyltransferase inhibitors are effective HbF inducers, however was not currently approved for β-thalassemia treatments. Here we report that the newly developed non-nucleoside DNMT1 inhibitor DMT207 strongly reactivates the expression of HbF in HUDEP-2 cells and adult primary erythroblasts with minimal toxicity. Moreover, in a mouse model of β-thalassemia, the administration of DMT207 effectively induces the expression of mouse fetal- and embryonic-type hemoglobin, promotes the maturation of erythroid cells, and alleviates the splenomegaly of mice. Further multi-omics studies expose γ-globin as one of the most sensitive genes in response to DMT207 treatment. Mechanistically, DMT207 inhibits DNMT1 enzymatic activity through trapping DNMT1 into an open conformation and meanwhile enhances interactions between the conformationally-kinked DNMT1 and UHRF1, partially contributing to specific degradation of DNMT1. Thus, we conclude that DMT207 is a promising novel DNMT1 inhibitor that could benefit patients with β-thalassemia.
2026-03-04 | GSE298943 | GEO
Project description:The β-thalassemia is a recessively inherited disease affecting millions around the world. Pharmacological induction of fetal hemoglobin (HbF) is an effective therapeutic strategy for the management of β-thalassemia. DNA methyltransferase inhibitors are effective HbF inducers, however was not currently approved for β-thalassemia treatments. Here we report that the newly developed non-nucleoside DNMT1 inhibitor DMT207 strongly reactivates the expression of HbF in HUDEP-2 cells and adult primary erythroblasts with minimal toxicity. Moreover, in a mouse model of β-thalassemia, the administration of DMT207 effectively induces the expression of mouse fetal- and embryonic-type hemoglobin, promotes the maturation of erythroid cells, and alleviates the splenomegaly of mice. Further multi-omics studies expose γ-globin as one of the most sensitive genes in response to DMT207 treatment. Mechanistically, DMT207 inhibits DNMT1 enzymatic activity through trapping DNMT1 into an open conformation and meanwhile enhances interactions between the conformationally-kinked DNMT1 and UHRF1, partially contributing to specific degradation of DNMT1. Thus, we conclude that DMT207 is a promising novel DNMT1 inhibitor that could benefit patients with β-thalassemia.
2026-03-04 | GSE298942 | GEO
Project description:The β-thalassemia is a recessively inherited disease affecting millions around the world. Pharmacological induction of fetal hemoglobin (HbF) is an effective therapeutic strategy for the management of β-thalassemia. DNA methyltransferase inhibitors are effective HbF inducers, however was not currently approved for β-thalassemia treatments. Here we report that the newly developed non-nucleoside DNMT1 inhibitor DMT207 strongly reactivates the expression of HbF in HUDEP-2 cells and adult primary erythroblasts with minimal toxicity. Moreover, in a mouse model of β-thalassemia, the administration of DMT207 effectively induces the expression of mouse fetal- and embryonic-type hemoglobin, promotes the maturation of erythroid cells, and alleviates the splenomegaly of mice. Further multi-omics studies expose γ-globin as one of the most sensitive genes in response to DMT207 treatment. Mechanistically, DMT207 inhibits DNMT1 enzymatic activity through trapping DNMT1 into an open conformation and meanwhile enhances interactions between the conformationally-kinked DNMT1 and UHRF1, partially contributing to specific degradation of DNMT1. Thus, we conclude that DMT207 is a promising novel DNMT1 inhibitor that could benefit patients with β-thalassemia.
2026-03-04 | GSE298941 | GEO
Project description:Expression profiling of neonatl rat ventricular cardiomyocytes (NRVMs) upon the treatement of Class IIa HDAC inhibitor
2019-04-23 | GSE130150 | GEO
Project description:Background: Ewing sarcoma (EwS) are characterized by oncogenic chimeric EWS-ETS proteins. EZH2 is upregulated via predominant EWS-FLI1 in EwS. RNAi of EZH2 revealed an EZH2-maintained, undifferentiated, stemness phenotype. Herein, microarray analysis demonstrated that treatment with HDAC inhibitors (HDACi) entinostat or TSA resulted in the induction of a similar pattern of differentiation genes as observed after EZH2 RNAi. This indicates that EZH2-containing PRC2 complexes may serve as a building block of class I HDAC activity in EwS. Methods: The role of class I HDACs was determined using different inhibitors including TSA, romidepsin (FK228), entinostat (MS-275) and PCI-34051 as well as CRISPR/Cas9 class I HDAC knock outs and HDAC RNAi. To analyze resulting changes microarray and gene set enrichment analysis (GSEA), qRT-PCR, western blotting, Co-IP, proliferation, apoptosis, differentiation, invasion assays and xenograft-mouse models were used. Results: Class I HDACs are constitutively expressed in EwS. They seem regulated via EWS-FLI1. Interestingly, patients with high levels of individual class I HDAC expression show decreased overall survival. CRISPR/Cas9 class I HDAC knock out of individual HDACs such as HDAC1 and HDAC2 inhibited growth, invasiveness, and blocked local tumor growth in xenograft mice. Microarray and GSEA analysis demonstrated that treatment with individual HDAC inhibitors (HDACi) blocked an EWS-FLI1 specific expression profile, while entinostat in addition suppressed metastasis relevant genes. EwS cells demonstrated increased susceptibility to treatment with first line chemotherapeutics including doxorubicin in the presence of HDACi. Furthermore, HDACi treatment mimicked RNAi of EZH2 in EwS. Treated cells showed diminished growth capacity, but an increased endothelial as well as neuronal differentiation ability. HDACi synergizes with EED inhibitor (EEDi) in vitro and together inhibited tumor growth in xenograft mice. Co-IP experiments identified HDAC class I family members as part of a regulatory complex together with PRC2. Conclusion: Class I HDAC proteins seem to be important mediators of the pathognomonic EWS-ETS-mediated transcription program in EwS and in combination therapy, co-treatment with HDACi are interesting new treatment opportunities for this malignant disease.
2021-10-20 | GSE162788 | GEO
Project description:Background: Ewing sarcoma (EwS) are characterized by oncogenic chimeric EWS-ETS proteins. EZH2 is upregulated via predominant EWS-FLI1 in EwS. RNAi of EZH2 revealed an EZH2-maintained, undifferentiated, stemness phenotype. Herein, microarray analysis demonstrated that treatment with HDAC inhibitors (HDACi) entinostat or TSA resulted in the induction of a similar pattern of differentiation genes as observed after EZH2 RNAi. This indicates that EZH2-containing PRC2 complexes may serve as a building block of class I HDAC activity in EwS. Methods: The role of class I HDACs was determined using different inhibitors including TSA, romidepsin (FK228), entinostat (MS-275) and PCI-34051 as well as CRISPR/Cas9 class I HDAC knock outs and HDAC RNAi. To analyze resulting changes microarray and gene set enrichment analysis (GSEA), qRT-PCR, western blotting, Co-IP, proliferation, apoptosis, differentiation, invasion assays and xenograft-mouse models were used. Results: Class I HDACs are constitutively expressed in EwS. They seem regulated via EWS-FLI1. Interestingly, patients with high levels of individual class I HDAC expression show decreased overall survival. CRISPR/Cas9 class I HDAC knock out of individual HDACs such as HDAC1 and HDAC2 inhibited growth, invasiveness, and blocked local tumor growth in xenograft mice. Microarray and GSEA analysis demonstrated that treatment with individual HDAC inhibitors (HDACi) blocked an EWS-FLI1 specific expression profile, while entinostat in addition suppressed metastasis relevant genes. EwS cells demonstrated increased susceptibility to treatment with first line chemotherapeutics including doxorubicin in the presence of HDACi. Furthermore, HDACi treatment mimicked RNAi of EZH2 in EwS. Treated cells showed diminished growth capacity, but an increased endothelial as well as neuronal differentiation ability. HDACi synergizes with EED inhibitor (EEDi) in vitro and together inhibited tumor growth in xenograft mice. Co-IP experiments identified HDAC class I family members as part of a regulatory complex together with PRC2. Conclusion: Class I HDAC proteins seem to be important mediators of the pathognomonic EWS-ETS-mediated transcription program in EwS and in combination therapy, co-treatment with HDACi are interesting new treatment opportunities for this malignant disease.
2021-10-20 | GSE162786 | GEO
Project description:Background: Ewing sarcoma (EwS) are characterized by oncogenic chimeric EWS-ETS proteins. EZH2 is upregulated via predominant EWS-FLI1 in EwS. RNAi of EZH2 revealed an EZH2-maintained, undifferentiated, stemness phenotype. Herein, microarray analysis demonstrated that treatment with HDAC inhibitors (HDACi) entinostat or TSA resulted in the induction of a similar pattern of differentiation genes as observed after EZH2 RNAi. This indicates that EZH2-containing PRC2 complexes may serve as a building block of class I HDAC activity in EwS. Methods: The role of class I HDACs was determined using different inhibitors including TSA, romidepsin (FK228), entinostat (MS-275) and PCI-34051 as well as CRISPR/Cas9 class I HDAC knock outs and HDAC RNAi. To analyze resulting changes microarray and gene set enrichment analysis (GSEA), qRT-PCR, western blotting, Co-IP, proliferation, apoptosis, differentiation, invasion assays and xenograft-mouse models were used. Results: Class I HDACs are constitutively expressed in EwS. They seem regulated via EWS-FLI1. Interestingly, patients with high levels of individual class I HDAC expression show decreased overall survival. CRISPR/Cas9 class I HDAC knock out of individual HDACs such as HDAC1 and HDAC2 inhibited growth, invasiveness, and blocked local tumor growth in xenograft mice. Microarray and GSEA analysis demonstrated that treatment with individual HDAC inhibitors (HDACi) blocked an EWS-FLI1 specific expression profile, while entinostat in addition suppressed metastasis relevant genes. EwS cells demonstrated increased susceptibility to treatment with first line chemotherapeutics including doxorubicin in the presence of HDACi. Furthermore, HDACi treatment mimicked RNAi of EZH2 in EwS. Treated cells showed diminished growth capacity, but an increased endothelial as well as neuronal differentiation ability. HDACi synergizes with EED inhibitor (EEDi) in vitro and together inhibited tumor growth in xenograft mice. Co-IP experiments identified HDAC class I family members as part of a regulatory complex together with PRC2. Conclusion: Class I HDAC proteins seem to be important mediators of the pathognomonic EWS-ETS-mediated transcription program in EwS and in combination therapy, co-treatment with HDACi are interesting new treatment opportunities for this malignant disease.
2021-10-20 | GSE162785 | GEO
Project description:In this project, we transfected MC38 cells with Flag-tagged Mbtps1 or vector control. After that, we performed immunoprecipitation–mass spectrometry analysis to search the interacting proteins of MBTPS1. In our study, We observed that the loss of membrane-bound transcription factor site-1 protease (MBTPS1) in tumor cells enhanced antitumor immunity and potentiated anti-PD-1 therapy. Mechanistic studies revealed that tumor cell-intrinsic MBTPS1 competed with USP13 for binding to STAT1, thereby disrupting USP13-dependent deubiquitination and stabilization of STAT1. MBTPS1 deficiency induced CXCR3+ CD8+ T cell infiltration by upregulating STAT1-transcribed chemokines including CXCL9, CXCL10 and CXCL11. Notably, the regulatory role of MBTPS1 in antitumor immunity operates independently of its classic function in cleaving membrane-bound transcription factors. Collectively, our results provide a theoretical basis for MBTPS1 as a potential immunotherapy target and also as a predictor of immunotherapy efficacy.
2025-04-11 | PXD053978 | Pride
Project description:Identification of the all RNA species associated with DNMT1. Using a comparative genome-scale approach we identified and correlated the RNA species physically associated with DNMT1 and proximal to the annotated genes to the methylation status of the corresponding loci and expression levels of the respective genes. This comparative approach delineated the first -DNMT1 centered- 'epitranscriptome' map, a comprehensive map cross-referencing DNMT1-interacting transcripts to (i) DNA methylation and (ii) gene expression profile. Relationship between DNMT1-RNA interactions, DNA methylation and gene expression
2012-12-01 | E-GEOD-32162 | biostudies-arrayexpress