Similar Datasets
Project description:E1A binding protein (p300) and CREB binding protein (CBP) are two homologous histone acetyl transferases that co-activate key oncogenes such as MYC and IRF4, which are relevant transcription factors in a number of haematological malignancies. In this work, we studied the effects of CCS1477 (also known as Inobrodib), a first in class orally available inhibitor of the p300/CBP bromodomains. We found that this compound causes cell cycle arrest in a panel of different hematologic cell lines and primary samples, together with a concomitant induction of myeloid differentiation in most of the AML samples. Mechanistically, we discovered that 6 hours exposure to CCS1477 triggers a rapid and selective loss of EP300 from MYB-bound enhancers in THP1 AML cells. Interestingly, after 48 hours treatment EP300 redistributes to alternate sites to induce up regulation of differentiation genes. Displacement of EP300 from MYB-bound enhancers is significantly associated with the rapid collapse in the expression of nearby genes, most of which correspond to key myeloid identity transcription factors such as MYC, MYB, CEBPA, GFI1, SPI1 and IRF8. In most of these down-regulated genes after CCS1477 treatment, the RNA-Pol II is stalled along the gene body thus failing in completing the transcriptional elongation. In OPM2 myeloma cells, CCS1477 releases EP300 from FGFR3, the target of the common (4;14) translocation, with loss of EP300 from enhancer sites bound by IRF4. We also showed that in leukaemia patients this drug causes a substantial increase in blood neutrophil count and up-regulation of MYB-regulated differentiation genes in the population of blast cells, while in myeloma patients it conferred a sustained reduction in urinary free light chains. Overall, our study describes the molecular activity of a novel epigenetic drug in different haematological malignancy settings, with promising effects in vivo both as single agent and in combination with standard of care agents such as azacitidine and venetoclax.
2023-11-28 | GSE207355 | GEO
Project description:E1A binding protein (p300) and CREB binding protein (CBP) are two homologous histone acetyl transferases that co-activate key oncogenes such as MYC and IRF4, which are relevant transcription factors in a number of haematological malignancies. In this work, we studied the effects of CCS1477 (also known as Inobrodib), a first in class orally available inhibitor of the p300/CBP bromodomains. We found that this compound causes cell cycle arrest in a panel of different hematologic cell lines and primary samples, together with a concomitant induction of myeloid differentiation in most of the AML samples. Mechanistically, we discovered that 6 hours exposure to CCS1477 triggers a rapid and selective loss of EP300 from MYB-bound enhancers in THP1 AML cells. Interestingly, after 48 hours treatment EP300 redistributes to alternate sites to induce up regulation of differentiation genes. Displacement of EP300 from MYB-bound enhancers is significantly associated with the rapid collapse in the expression of nearby genes, most of which correspond to key myeloid identity transcription factors such as MYC, MYB, CEBPA, GFI1, SPI1 and IRF8. In most of these down-regulated genes after CCS1477 treatment, the RNA-Pol II is stalled along the gene body thus failing in completing the transcriptional elongation. In OPM2 myeloma cells, CCS1477 releases EP300 from FGFR3, the target of the common (4;14) translocation, with loss of EP300 from enhancer sites bound by IRF4. We also showed that in leukaemia patients this drug causes a substantial increase in blood neutrophil count and up-regulation of MYB-regulated differentiation genes in the population of blast cells, while in myeloma patients it conferred a sustained reduction in urinary free light chains. Overall, our study describes the molecular activity of a novel epigenetic drug in different haematological malignancy settings, with promising effects in vivo both as single agent and in combination with standard of care agents such as azacitidine and venetoclax.
2023-11-28 | GSE207354 | GEO
Project description:E1A binding protein (p300) and CREB binding protein (CBP) are two homologous histone acetyl transferases that co-activate key oncogenes such as MYC and IRF4, which are relevant transcription factors in a number of haematological malignancies. In this work, we studied the effects of CCS1477 (also known as Inobrodib), a first in class orally available inhibitor of the p300/CBP bromodomains. We found that this compound causes cell cycle arrest in a panel of different hematologic cell lines and primary samples, together with a concomitant induction of myeloid differentiation in most of the AML samples. Mechanistically, we discovered that 6 hours exposure to CCS1477 triggers a rapid and selective loss of EP300 from MYB-bound enhancers in THP1 AML cells. Interestingly, after 48 hours treatment EP300 redistributes to alternate sites to induce up regulation of differentiation genes. Displacement of EP300 from MYB-bound enhancers is significantly associated with the rapid collapse in the expression of nearby genes, most of which correspond to key myeloid identity transcription factors such as MYC, MYB, CEBPA, GFI1, SPI1 and IRF8. In most of these down-regulated genes after CCS1477 treatment, the RNA-Pol II is stalled along the gene body thus failing in completing the transcriptional elongation. In OPM2 myeloma cells, CCS1477 releases EP300 from FGFR3, the target of the common (4;14) translocation, with loss of EP300 from enhancer sites bound by IRF4. We also showed that in leukaemia patients this drug causes a substantial increase in blood neutrophil count and up-regulation of MYB-regulated differentiation genes in the population of blast cells, while in myeloma patients it conferred a sustained reduction in urinary free light chains. Overall, our study describes the molecular activity of a novel epigenetic drug in different haematological malignancy settings, with promising effects in vivo both as single agent and in combination with standard of care agents such as azacitidine and venetoclax.
2023-11-28 | GSE207353 | GEO
Project description:E1A binding protein (p300) and CREB binding protein (CBP) are two homologous histone acetyl transferases that co-activate key oncogenes such as MYC and IRF4, which are relevant transcription factors in a number of haematological malignancies. In this work, we studied the effects of CCS1477 (also known as Inobrodib), a first in class orally available inhibitor of the p300/CBP bromodomains. We found that this compound causes cell cycle arrest in a panel of different hematologic cell lines and primary samples, together with a concomitant induction of myeloid differentiation in most of the AML samples. Mechanistically, we discovered that 6 hours exposure to CCS1477 triggers a rapid and selective loss of EP300 from MYB-bound enhancers in THP1 AML cells. Interestingly, after 48 hours treatment EP300 redistributes to alternate sites to induce up regulation of differentiation genes. Displacement of EP300 from MYB-bound enhancers is significantly associated with the rapid collapse in the expression of nearby genes, most of which correspond to key myeloid identity transcription factors such as MYC, MYB, CEBPA, GFI1, SPI1 and IRF8. In most of these down-regulated genes after CCS1477 treatment, the RNA-Pol II is stalled along the gene body thus failing in completing the transcriptional elongation. In OPM2 myeloma cells, CCS1477 releases EP300 from FGFR3, the target of the common (4;14) translocation, with loss of EP300 from enhancer sites bound by IRF4. We also showed that in leukaemia patients this drug causes a substantial increase in blood neutrophil count and up-regulation of MYB-regulated differentiation genes in the population of blast cells, while in myeloma patients it conferred a sustained reduction in urinary free light chains. Overall, our study describes the molecular activity of a novel epigenetic drug in different haematological malignancy settings, with promising effects in vivo both as single agent and in combination with standard of care agents such as azacitidine and venetoclax.
2023-11-28 | GSE207356 | GEO
Project description:Covalent modification of histones is a fundamental mechanism of regulated gene expression in eukaryotes, and interpretation of histone modifications is an essential feature of epigenetic control. Bromodomains are specialized binding modules that interact with acetylated histones, linking chromatin recognition to gene transcription. Because of their ability to function in a domain-specific fashion, selective disruption of bromodomain:acetylated histone interactions with chemical probes serves as a powerful means for understanding biological processes regulated by these chromatin adaptors. Here we describe the discovery and characterization of potent and selective small molecule inhibitors for the bromodomains of CREBBP/EP300 that engage their target in cellular assays. We use these tools to demonstrate a critical role for CREBBP/EP300 bromodomains in regulatory T cell biology. Because regulatory T cell recruitment to tumors is a major mechanism of immune evasion by cancer cells, our data highlight the importance of CREBBP/EP300 bromodomain inhibition as a novel, small molecule-based approach for cancer immunotherapy.
| S-EPMC4933219 | biostudies-literature
Project description:Silencing of the somatic cell type-specific genes is a critical yet poorly understood step in reprogramming. To uncover pathways that maintain cell identity, we performed a reprogramming screen using inhibitors of chromatin factors. Here, we identify acetyl-lysine competitive inhibitors targeting the bromodomains of coactivators CREB (cyclic-AMP response element binding protein) binding protein (CBP) and E1A binding protein of 300 kDa (EP300) as potent enhancers of reprogramming. These inhibitors accelerate reprogramming, are critical during its early stages and, when combined with DOT1L inhibition, enable efficient derivation of human induced pluripotent stem cells (iPSCs) with OCT4 and SOX2. In contrast, catalytic inhibition of CBP/EP300 prevents iPSC formation, suggesting distinct functions for different coactivator domains in reprogramming. CBP/EP300 bromodomain inhibition decreases somatic-specific gene expression, histone H3 lysine 27 acetylation (H3K27Ac) and chromatin accessibility at target promoters and enhancers. The master mesenchymal transcription factor PRRX1 is one such functionally important target of CBP/EP300 bromodomain inhibition. Collectively, these results show that CBP/EP300 bromodomains sustain cell-type-specific gene expression and maintain cell identity.
| S-EPMC6504645 | biostudies-literature
Project description:In advanced prostate cancer, CREB (cAMP-responsive element-binding protein) binding protein (CBP) and its homolog EP300 are highly expressed; targeting the bromodomain of CBP is a new strategy for the treatment of prostate cancer. In the current study we identified Y08197, a novel 1-(indolizin-3-yl) ethanone derivative, as a selective inhibitor of CBP/EP300 bromodomain and explored its antitumor activity against prostate cancer cell lines in vitro. In the AlphaScreen assay, we demonstrated that Y08197 dose-dependently inhibited the CBP bromodomain with an IC50 value at 100.67?±?3.30?nM. Y08197 also exhibited high selectivity for CBP/EP300 over other bromodomain-containing proteins. In LNCaP, 22Rv1 and VCaP prostate cancer cells, treatment with Y08197 (1, 5??M) strongly affected downstream signaling transduction, thus markedly inhibiting the expression of androgen receptor (AR)-regulated genes PSA, KLK2, TMPRSS2, and oncogenes C-MYC and ERG. Notably, Y08197 potently inhibited cell growth in several AR-positive prostate cancer cell lines including LNCaP, 22Rv1, VCaP, and C4-2B. In 22Rv1 prostate cancer cells, treatment with Y08197 (1, 4, 16??M) dose-dependently induced G0/G1 phase arrest and apoptosis. Furthermore, treatment with Y08197 (5??M) significantly decreased ERG-induced invasive capacity of 22Rv1 prostate cancer cells detected in wound-healing assay and cell migration assay. Taken together, CBP/EP300 inhibitor Y08197 represents a promising lead compound for development as new therapeutics for the treatment of castration-resistant prostate cancer.
| S-EPMC6889168 | biostudies-literature
Project description:CBP and EP300 are highly homologous, bromodomain-containing transcription coactivators involved in numerous cellular pathways relevant to oncology. As part of our effort to explore the potential therapeutic implications of selectively targeting bromodomains, we set out to identify a CBP/EP300 bromodomain inhibitor that was potent both in vitro and in cellular target engagement assays and was selective over the other members of the bromodomain family. Reported here is a series of cell-potent and selective probes of the CBP/EP300 bromodomains, derived from the fragment screening hit 4-methyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-one.
| S-EPMC4867486 | biostudies-literature
Project description:Bromodomain and extra-terminal domain (BET) proteins, cyclic adenosine monophosphate response element-binding protein (CBP), and the E1A-binding protein of p300 (EP300) are important players in histone acetylation. Preclinical evidence supports the notion that small molecules targeting these proteins individually or in combination can elicit antitumor activity. Here, we characterize the antitumor activity of the pan BET/CBP/EP300 inhibitor NEO2734 and provide insights into its mechanism of action through bromodomain-binding assays, in vitro and in vivo treatments of cancer cell lines, immunoblotting, and transcriptome analyses. In a panel of 60 models derived from different tumor types, NEO2734 exhibited antiproliferative activity in multiple cell lines, with the most potent activity observed in hematologic and prostate cancers. Focusing on lymphoma cell lines, NEO2374 exhibited a pattern of response and transcriptional changes similar to lymphoma cells exposed to either BET or CBP/EP300 inhibitors alone. However, NEO2734 was more potent than single-agent BET or CBP/EP300 inhibitors alone. In conclusion, NEO2734 is a novel antitumor compound that shows preferential activity in lymphomas, leukemias, and prostate cancers.
| S-EPMC7479962 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-05-31 | GSE124333 | GEO