CPI-203

The bromodomain inhibitor CPI203 induced relatively consistent effects on gene expression and growth across a variety of glioblastoma lines, specifically down-regulating genes associated with DNA replication. We propose that clinically effective BET inhibitors have the potential to induce consistent beneficial effects across a spectrum of glioblastomas.

Here we undertook the simultaneous evaluation of two epigenetic drugs targeting EZH2 methyltransferase activity and BRD4-mediated control of MYC transcription, CPI169 and CPI203, using preclinical models of DLBCL and FL with distinct EZH2 mutational status. Gene expression profile, exploratory data analysis, and siRNA screening identified the PI3K/AKT-regulated gene and mitosis regulator, YPEL2, as a crucial factor involved in the efficacy of MYC/EZH2 dual targeting both in vitro and in vivo. Altogether, our results provide first pre-clinical evidence that simultaneous targeting of MYC and EZH2 is a safe and efficient approach that can be monitored by specific biomarkers, in aggressive lymphoid tumors of germinal center origin.

Given the known interplay between EZH2 and MYC downstream signaling in malignant B cells, we undertook the simultaneous evaluation of two epigenetic drugs that interfere with EZH2 methyltransferase activity and BRD4-mediated control of MYC transcription, namely CPI169 and CPI203; using preclinical models of DLBCL and FL with distinct EZH2 mutational status. Gene expression profile analysis, followed by automated exploratory data analysis and validation by a siRNA screening, further identified the PI3K/AKT-regulated gene and mitosis regulator, YPEL2; as a crucial factor involved in the efficacy of MYC/EZH2 dual targeting in vitro and in vivo . Conclusion These results provide a first preclinical evidence that simultaneous targeting of MYC and EZH2 is a safe and efficient approach that can be monitored by specific biomarkers in aggressive lymphoid tumors of germinal center origin.

A Combination of CHCP and CPI203, a BET bromodomain inhibitor, and a BCL2A1 antagonist increased the CHCP-induced cell death (p < 0.05). Our results revealed that BCL2A1 is a key gene for resistance during CHCP induced cell death. This resistance in TNBCs could be reversed with a combination of siRNA or BCL2A1 antagonist-CHCP therapy.

Cell-transfection and the chromatin immunoprecipitation assay manifested that BRD4 plays a key role in PD-L1 expression, CPI-203 can inhibit the expression of PD-L1 by inhibiting the BRD4 occupation of the PD-L1 promoter region. This study indicates a potential clinical immunotherapy method to reduce the incidence of clinical resistance to immunotherapy in HCC patients.

The data gathered with CPI-203 were compared with the BRD4-degrading PROTAC A1874, used alone or in combination with the 14G2a mAb. Conclusion Research on combined targeting of GD2 and BRD4 in MYCN -amplified NB cells adds to efforts to pre-clinically evaluate new combined treatment approaches, aiming to improve survival of the high-risk neuroblastoma patients.

The data gathered with CPI-203 were compared with the BRD4-degrading PROTAC A1874, used alone or in combination with the 14G2a mAb. Conclusion Research on combined targeting of GD2 and BRD4 in MYCN -amplified NB cells adds to efforts to pre-clinically evaluate new combined treatment approaches, aiming to improve survival of the high-risk neuroblastoma patients.

The data gathered with CPI-203 were compared with the BRD4-degrading PROTAC A1874, used alone or in combination with the 14G2a mAb. Conclusion Research on combined targeting of GD2 and BRD4 in MYCN -amplified NB cells adds to efforts to pre-clinically evaluate new combined treatment approaches, aiming to improve survival of the high-risk neuroblastoma patients.

The data gathered with CPI-203 were compared with the BRD4-degrading PROTAC A1874, used alone or in combination with the 14G2a mAb. Conclusion Research on combined targeting of GD2 and BRD4 in MYCN -amplified NB cells adds to efforts to pre-clinically evaluate new combined treatment approaches, aiming to improve survival of the high-risk neuroblastoma patients.

Three human PCa cell lines, PC-3, LNCaP, and C42B, were selected and treated with IC50 value of I-BET762, I-BET726, and CPI-203, respectively. PCa is closely related to histone crotonylation. Inhibition of BRD4 expression can inhibit the proliferation, migration, and invasion of PCa cells.

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.