I-BET151

We aimed to explore the synergistic efficacy of the bromodomain-containing protein 4 (BRD4) inhibitor I-BET151 in combination with RT for GBM therapy...In conclusion, BRD4 contributes to extracellular matrix remodeling and radioresistance in a SE-driven COL1A1-dependent manner. Thus, targeting BRD4 is a rational strategy to augment the efficacy of RT for GBM treatment.

The results presented here suggest that BET inhibition therapy should be used with caution due to possible bimodal effects at high concentrations at the detriment of pancreatic beta cell function.

Guided by scaffold hopping strategy, key pharmacophore of BRD4 inhibitor I-BET-151 was incorporated into an in-house developed HDAC3-selective inhibitor 17h...Compound 26n demonstrated significant antitumor efficacy in Capan-1 CDX model, with a tumor growth inhibition rate of 71 % under the given dosing regimen. In summary, this research highlights the promising therapeutic potential of benzodihydroindazole derivatives as HDAC3/BRD4 dual inhibitors, warranting further investigation.

Our results strongly support precision therapies for MPNSTs guided by TSG inactivation status. MEKi-BETi-CDKi triple treatment elicits a significant reduction of human MPNST PDOX.

High LPAR1 expression also correlated with increased sensitivity to compounds, such as BET bromodomain inhibitors I-BET151 and RITA, suggesting LPAR1 as a biomarker for predicting drug activity...These findings suggest that LPAR1 is a critical regulator of paraptosis in GC and a potential biomarker for drug sensitivity and immunotherapy response. This underscores the role of CAFs in mediating tumorigenic effects and suggests that targeting LPAR1 could be a promising strategy for precision medicine in GC.

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.