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Safety and Efficacy of Bromodomain and Extra-Terminal Inhibitors for the Treatment of Hematological Malignancies and Solid Tumors: A Systematic Study of Clinical Trials

Background: The upregulated expression of BET proteins is closely associated with the occurrence and development of hematological malignancies and solid tumors. Several BET inhibitors have been developed, and some have been in phase I/II of clinical trials. Here, the safety, efficacy, and pharmacodynamics of ten BET inhibitors currently in clinical trials were evaluated. 

Methods: We retrieved and reviewed published reports on the clinical trials of twelve BET inhibitors including AZD5153, ABBV-075, BMS-986158, CPI-0610, GSK525762, OTX-015, PLX51107, INCB054329, INCB057643, FT-1101, CC-90010, and ODM-207 for patients with hematological malignancies and solid tumors and summarized their published target genes. 

Results: In the monotherapy of BET inhibitors, the most common and severe (grade ≥3) hematological adverse events (AEs) are thrombocytopenia, anemia, and neutropenia. The most common non-hematological syndromes are diarrhea, nausea, fatigue, dysgeusia, and decreased appetite, while the most severe AE is pneumonia. Additionally, T max of these BET inhibitors was between 0.5-6 h, but the range for T 1/2 varied significantly. According to published data, the rates of SD, PD, CR and PR were 27.4%, 37.6%, 3.5%, and 5.7%, respectively, which is not very satisfactory. In addition to BRD4, oncogene MYC is another common target gene of these BET inhibitors. Ninety-seven signaling pathways may be regulated by BET inhibitors. 

Conclusion: All BET inhibitors reviewed in our study exhibited exposure-dependent thrombocytopenia, which may limit their clinical application. Moreover, further efforts are necessary to explore the optimal dosing schemes and combinations to maximize the efficacy of BET inhibitors.

 

Comments:

The passage you provided summarizes the evaluation of twelve BET inhibitors currently undergoing clinical trials for the treatment of hematological malignancies and solid tumors. These inhibitors target BET proteins, which are known to be upregulated in various types of cancer. The study assessed the safety, efficacy, and pharmacodynamics of these inhibitors based on published reports.

In terms of safety, the most common and severe hematological adverse events observed with the monotherapy of BET inhibitors were thrombocytopenia (low platelet count), anemia, and neutropenia (low neutrophil count). Among the non-hematological side effects, diarrhea, nausea, fatigue, dysgeusia (altered taste), and decreased appetite were commonly reported. Pneumonia was identified as the most severe adverse event. These findings suggest that BET inhibitors can have significant effects on blood cells and may cause gastrointestinal and general systemic side effects.

The pharmacokinetic properties of the BET inhibitors varied. The time taken to reach maximum concentration (T max) ranged from 0.5 to 6 hours. However, the half-life (T 1/2) of these inhibitors showed significant variation, indicating differences in their duration of action within the body.

The efficacy of the BET inhibitors, as indicated by published data, was not considered very satisfactory. The rates of stable disease (SD), progressive disease (PD), complete response (CR), and partial response (PR) were reported as 27.4%, 37.6%, 3.5%, and 5.7%, respectively. This suggests that while some patients experienced disease stabilization or partial response, a significant proportion did not respond or experienced disease progression.

The study also revealed that the common target genes of these BET inhibitors, in addition to BRD4, included the oncogene MYC. Furthermore, it was identified that these inhibitors may regulate a total of 97 signaling pathways, indicating their potential for influencing various cellular processes and cancer-related pathways.

In conclusion, the evaluated BET inhibitors exhibited exposure-dependent thrombocytopenia, which could pose limitations on their clinical application. The study suggests that further research is needed to optimize dosing regimens and explore combination therapies to maximize the efficacy of BET inhibitors in the treatment of hematological malignancies and solid tumors.

Related Products

Cat.No. Product Name Information
S8753 INCB054329 INCB054329 is a structurally distinct bromodomain and extraterminal domain (BET) inhibitor with IC50 values of 44 nM, 5 nM, 9 nM, 1 nM, 28 nM, 3 nM, 119 nM and 63 nM for BRD2-BD1, BRD2-BD2, BRD3-BD1, BRD3-BD2, BRD4-BD1, BRD4-BD2, BRDT-BD1 and BRDT-BD2, respectively.

Related Targets

Epigenetic Reader Domain