CPI-203

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.

These findings propose therapeutic strategies to address PARP inhibitor resistance using agents that are already approved or are in clinical development, with the potential for rapid translation to benefit a broad population of ovarian cancer patients.

Furthermore, the combinatorial screening identified a bromo- and extra-terminal domain (BET) inhibitor that could further improve H4-dependent leukemic differentiation in FLT3 wild-type monocytic AML. Taken together, this illustrates the value of an unbiased and multiplex screening platform for developing combinatorial therapeutic approaches for AML.

Biomarkers validation was made in vitro and in vivo, using a mouse xenotransplant model of EZH2mut DLBCL, considering both exposure to CPI169 single agent and/or combination treatment with a BRD4 inhibitor, CPI203...GEP analysis, followed by automated exploratory data analysis and validation by a siRNA screening, further identified the PI3K/AKT-regulated gene and mitosis regulator, YPEL2, and the regulator of innate-like B lymphocyte maturation, KLHL14, as crucial factors involved in the efficacy of MYC/EZH2 dual targeting. In conclusion, CPI169 shows significant activity and safety as single agent in EZH2 mutated-DLBCL and FL cases and displays synergistic interaction in vitro and in vivo with BRD4 inhibition, mediated by the modulation of a limited set of EZH2-regulated genes.

While subtle changes in chemistry around CFT-743 had negligible impact on vitro potency, the effect on therapeutic index was significant.In vitro, CFT-743 is more potent than a BET inhibitor (AZD5153) and a CDK9 inhibitor (dinaciclib) in 100% and 97% of 38 leukemia lines tested...Pre-dosing mice with the CRBN binding molecule pomalidomide significantly attenuates CFT-743 activity (TGI 40%) rendering the observed efficacy on par with BET inhibitor CPI-203 (TGI 2%) and thus confirming superior efficacy is dependent on BET degradation...In normal tissues, CFT-743 promotes a similar rapid and near complete loss of BRD4, however; protein levels begin to recover ≤ 6hr post dose. This pharmacodynamic behavior provides a rationale as to why CFT-743 is efficacious and well tolerated.Collectively, these data highlight the in vivo features important for efficacy and tolerability with BET degraders and establish the relationships between degrader pharmacokinetics, target protein degradation and efficacy.

Our results indicate that melanoma cells can modify, in a different manner, the selenoprotein transcript levels, as a possible mechanism to control tumor progression. We suggest that the usage of diet and supplements containing selenium should be carefully used for patients with melanoma.