I-BET151

The BET inhibitor IBET151, combined with anti-CTLA-4, overcame innate ICB resistance however, sequential BET inhibition failed against acquired resistance in mouse models...BET proteins in melanoma may play an oncogenic role by inducing immune suppression and driving T cell dysfunction. The study demonstrates an effective combination for innately unresponsive melanoma patients to checkpoint inhibitor immunotherapy, yet highlights BET inhibitors' limitations in an acquired resistance context.

Through applying systematic bioinformatic analysis, we determined that out of 31 chromatin remodeling factors in six gastrointestinal cancers, only PR/SET domain 1 (PRDM1) showed both expression alteration and prognosis prediction. Analyses on pathways, therapies, and mediators showed that cell cycle, bromodomain inhibitor IBET151, and BET protein BRD4 were, respectively involved in PRDM1-high stomach cancer, while cell line experiments validated that PRDM1 knockdown in human stomach cancer cell line SNU-1 decreased its proliferation, BRD4 expression, and responsiveness to IBET151; accordingly, these results indicate the contribution by PRDM1 in stomach cancer formation and its association with BRD4 modulation as well as BET inhibitor treatment.

In our group’s previous study, human cell lines NALM-6 and SEM responded to SYK inhibition by Entospletinib (Ento) with proliferation suppression and apoptosis induction. Herein, we evaluated the effect of combined inhibition with pan-BET inhibitor I-BET151 (IBET) and evaluated their synergistic potential in canine and human B-ALL in vitro models... Canine and human B-ALL cell lines had similar responses to Ento and IBET single treatments, showing anti-proliferative effects on NALM-6, SEM, and GL-1. The inhibition of proliferation induced by Ento may act through the induction of apoptosis rather than cell cycle arrest. IBET induced both, strong apoptosis (except NALM-6) and cell cycle arrest.

In the PDA organoid-based screen, epigenetic inhibitors ITF2357 and I-BET151 are identified, which in combination with anti-PD-1 based therapy show considerably greater anti-tumor effect. The combinatorial treatment turns the TME from immunosuppressive to immunoactive, up-regulates the MHC-I antigen processing and presentation, and enhances the effector T cell activity. The standardized PDA organoid model has shown great promise to accelerate drug discovery for the immunosuppressive cancer.

Integrative chromatin and transcriptional analysis following inhibition of RUNX1 and NOTCH1 revealed a surprisingly widespread role of RUNX1 in the establishment of global H3K27ac levels and that RUNX1 is required by NOTCH1 for cooperative transcription activation of key NOTCH1 target genes including MYC, DTX1, HES4, IL7R, and NOTCH3. Super-enhancers were preferentially sensitive to RUNX1 knockdown and RUNX1-dependent super-enhancers were disrupted following the treatment of a pan-BET inhibitor, I-BET151.

Through a high-throughput drug screening (HTS) we identified thioridazine (TDZ) as an efficacious compound, but its use is limited by the huge blood brain barriers crossing and cardiotoxic effects...In attempt to target it, we tested novel drug combinations of venetoclax (VEN), a BCL- 2 inhibitor, with KMT2A-specific drugs, revealing that the Bromodomain and Extra-Terminal Domain (BET) inhibitor I-BET151, and the kinase inhibitor sunitinib, decreased BCL-2 family protein expression and synergized with VEN enhancing KMT2A -r AML cell death, also in the 3D model... Overall, this study identified novel drug combinations of KMT2A -selective drugs together with VEN converging in different but all mitochondrial apoptotic networks activation, supporting the use of VEN in this AML setting. We demonstrate that TDZ6 reduces the AML growth in vitro and an enlarged in vivo study will support its efficacy andsafety. This study highlights the importance of having a bona-fide model to test drugs and produce reliable results, to accelerate the introduction of targeted therapies for the life-threatening KMT2A -AML subgroup of pediatric AML.

In addition, several BRD4 inhibitors have been evaluated for therapeutic purposes as monotherapy or in combination with chemotherapy, radiotherapy, and immune therapies. Here, we provide a critical appraisal of studies evaluating various BRD4 inhibitors and degraders as novel treatment strategies against GBM.

Overall, our ex vivo and in vitro studies indicate that i-BET858 represents an optimal candidate to pursue further clinical validation for the treatment of HGSC.

BRD4-targeted drug PFI-1 and (BRD2, BRD3, and BRD4)-targeted drug I-BET-151 may have good inhibitory effects on the SW13 cell line. The findings of this study provide a partial basis for the role of BRD2, BRD3, and BRD4 in the occurrence and development of ACC. In addition, this study also provides new potential therapeutic targets for ACC, which can serve as a reference for future basic and clinical research.

Interestingly, chemoresistance against epidermal growth factor receptor (EGFR) inhibitors including erlotinib and gefitinib was also related to Met...Moreover, another BET protein inhibitor I-BET151, or BRD4 depletion, also inhibited NSCLC cell growth and downregulated Met...Moreover, JQ1 inhibited the growth of paired erlotinib-sensitive and resistant HCC827 cells in parallel with Met downregulation and PI3K/Akt signaling inactivation...These results suggested that targeting BET proteins inhibited NSCLC via downregulating Met and inactivating PI3K/AKT pathway. Our findings reveal a novel mechanism of BET proteins implicated in NSCLC progression with Met taken into consideration.

Our data provide insights into the prognostic role of BET family in GC and proposed BET inhibition as a therapeutic strategy for GC patients.

We evaluated the anti-lymphoma activity of the isoform-specific bivalent BET inhibitor AZD5153 (AZD) and the pan-BET inhibitor I-BET151 (I-BET) as single agents and in combination with SYK inhibitor Entospletinib (Ento) in vitro. Genes such as ADGRA2, MYB, TNFRSF11A, S100A10, PLEKHH3, DHRS2 and FOXP1-AS1 were identified as possible key regulators. Simultaneous inhibition of BET and SYK enhanced the anti-proliferative effects, and induced a combination-specific gene expression signature.

Thus, the goal of this study is to explore the molecular mechanisms behind promising epigenetic inhibitors in RMS, focusing on embryonal RMS, and to test these drugs in vivo in combination with vincristine. Our laboratory obtained a selection of epigenetic compounds from the Ontario Institute of Cancer Research (OICR) and Structural Genomics Consortium (SGC) that mainly target BET (BMS-986158, I-BET151, PLX51107) or HDAC (Apicidin, Domatinostat, Fimepinostat) proteins...Furthermore, the level of apoptosis in this cell line was higher after treatment with PLX51107 than after treatment with the positive control, doxorubicin (Figure 3)... Our data suggest that BET inhibitors may exploit an epigenetic weakness of ERMS, perhaps related to MYC amplification. In the future, we plan to conduct transcriptome assays to explore the mechanism of action of BET inhibitors in ERMS, and in vivo drug combination studies in an ERMS mosaic mouse model and patient-derived xenografts (PDXs).

These data support the carcinogenic potential of pepsin and proton pump expression in BE and reveal molecular pathways affected by their expression. Further study is warranted to investigate the role of these pathways in carcinogenesis associated with BE.

In summary, our data show the combination of iBET-151 and paclitaxel resulted in markedly higher anti-tumor effects compared with either treatment alone for GC. With further studies to validate the efficacy and biomarker explorations, the combination of iBET-151 and paclitaxel represents a promising therapeutic strategy in GC.

Our screening revealed that both the bromodomain and extra-terminal domain (BET) inhibitor, I-BET151, and kinase inhibitor, sunitinib, decreased the BCL-2 family protein expression and significantly synergized with venetoclax, enhancing KMT2A-r AML cell line death. Blasts t (6; 11) KMT2A-AFDN rearranged, both from cell lines and primary samples, were shown to be significantly highly responsive to the combination of venetoclax and thioridazine, with the synergy being induced by a dramatic increase of mitochondrial depolarization that triggered blast apoptosis...Overall, this study identified that, by high-throughput screening, the most KMT2A-selective drugs converged in different but all mitochondrial apoptotic network activation, supporting the use of venetoclax in this AML setting. The novel drug combinations here unveiled provide a rationale for evaluating these combinations in preclinical studies to accelerate the introduction of targeted therapies for the life-threatening KMT2A-AML subgroup of pediatric AML.

Collectively, our data suggest that iBET-151 is a potential therapeutic agent for GC, especially in combination with paclitaxel, and that WNT5B and IRS2 may predict iBET-151 sensitivity.

Especially, the combination of forskolin, ISX9, CHIR99021, I-BET151 and DAPT allows GBM cells to be reprogrammed into neurons, and this process does not experience an intermediate pluripotent state. The research on the anticancer mechanism of I-BET151 will lead to new treatment strategies for clinical cancer.

The BET inhibitor (IBET151) and CDK9 inhibitor (CDKI73) synergistically killed melanoma cells in vitro independent of their BRAF or NRAS mutation status...Survival analysis showed worse prognosis with high G2M, E2F or c-MYC gene signatures suggesting biomarkers of response of BET and CDK9 inhibitors in melanoma. This combination of epigenetic inhibitors targets multiple downstream genes leading to cell death of melanoma cells in vitro and in vivo and warrant further investigation for treatment of melanoma in patients not responding to current therapies.

Here, we found that BETi JQ1 and I-BET151 exerted anti-tumor effects in TNBC by decreasing IKBKE expression to attenuate NF-κB signaling. Altogether, our findings illustrated TNBC-activated macrophages conferred TNBC cells resistance to BETi via IL-6 or IL-10/STAT3/IKBKE/NF-κB axis. Blockade of IKBKE or double inhibition of BET and STAT3 might be a novel strategy for treatment of TNBC.

We found 460 genes in which iBET-151 and paclitaxel combination treatment changed more than single-treatment or no-treatment. Thus, additional functional studies are needed, but our results provide the first evidence of the synergistic effect between iBET-151 and paclitaxel in regulating the transcriptome of GC cells.

Furthermore, in intracranial models, I-BET151 eliminated U87 GICs' tumorigenicity. The outcomes of this research could be conducive to design clinical trials for treatment of glioma based on BRD4.

The dual inhibition of BET and CBP/EP300 has potential therapeutic benefits for patients with MM.

Significantly, A1874-induced anti-colon cancer cell activity was more potent than the known BRD4 inhibitors (JQ1, CPI203, and I-BET151). BRD4 degradation and p53 protein elevation, as well as apoptosis induction and oxidative stress were detected in A1874-treated colon cancer tissues. Together, A1874 inhibits colon cancer cell growth through both BRD4-dependent and -independent mechanisms.

We identify HH/GLI signaling as a novel druggable pathway in EAC as well as validate an ability of clinically relevant GLI inhibitor to attenuate the viability of vismodegib-resistant EAC cells. Therefore, we propose that selective bromodomain inhibitors, such as IBET-151, could be used as novel therapeutic agents for EAC patients harboring GLI-dependent tumors.

Pan- and isoform-specific BET inhibitors applied as mono substances in low concentrations restrain cell proliferation and induce apoptosis/necrosis on CLBL-1. CLBL-1 is resistant to Entospletinib used as monotherapy. Combining Entospletinib with I-BET151 or AZD5153 does not significantly enhance antiproliferative effect and induction of apoptosis/necrosis toward CLBL-1.

Pan- and isoform-specific BET inhibitors applied as mono substances in low concentrations restrain cell proliferation and induce apoptosis/necrosis on CLBL-1. CLBL-1 is resistant to Entospletinib used as monotherapy. Combining Entospletinib with I-BET151 or AZD5153 does not significantly enhance antiproliferative effect and induction of apoptosis/necrosis toward CLBL-1.

Pan- and isoform-specific BET inhibitors applied as mono substances in low concentrations restrain cell proliferation and induce apoptosis/necrosis on CLBL-1. CLBL-1 is resistant to Entospletinib used as monotherapy. Combining Entospletinib with I-BET151 or AZD5153 does not significantly enhance antiproliferative effect and induction of apoptosis/necrosis toward CLBL-1.

Entospletinib did not enhance the inhibitory effects of the pan- or isoform-specific BET.

We report that BET and CDK9 inhibitor iBET151 and CDKI73 synergistically killed melanoma cells independent of their genetic background compared to single inhibitors... Our findings have revealed that this novel combination of two epigenetic inhibitors targets multiple downstream genes associated with cell cycle, oncogenesis and, apoptotic pathways which augments cell death compared to effects of the single drugs. Overall, the findings warrant further investigation of key targets involved in the responses and the extent to which effects of CDK9 inhibition is due to effects on chromatin modelling. The combination would appear promising to consider for future clinical trial in melanoma patients not responding to current therapies.