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Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762
Aristeidis Chaidos1, Valentina Caputo, Katerina Gouvedenou
1Centre for Haematology, Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom;
Abstract:
The bromodomain and extraterminal (BET) protein BRD2-4 inhibitors hold therapeutic promise in preclinical models of hematologic malignancies. However, translation of these data to molecules suitable for clinical development has yet to be accomplished. Herein we expand the mechanistic understanding of BET inhibitors in multiple myeloma by using the chemical probe molecule I-BET151. I-BET151 induces apoptosis and exerts strong antiproliferative effect in vitro and in vivo. This is associated with contrasting effects on oncogenic MYC and HEXIM1, an inhibitor of the transcriptional activator P-TEFb. I-BET151 causes transcriptional repression of MYC and MYC-dependent programs by abrogating recruitment to the chromatin of the P-TEFb component CDK9 in a BRD2-4-dependent manner. In contrast, transcriptional upregulation of HEXIM1 is BRD2-4 independent. Finally, preclinical studies show that I-BET762 has a favorable pharmacologic profile as an oral agent and that it inhibits myeloma cell proliferation, resulting in survival advantage in a systemic myeloma xenograft model. These data provide a strong rationale for extending the clinical testing of the novel antimyeloma agent I-BET762 and reveal insights into biologic pathways required for myeloma cell proliferation.
Insights
Bromodomain and extraterminal (BET) inhibitors like I-BET762 show promise for treating multiple myeloma by suppressing cancer cell growth. These agents target key pathways, offering a rationale for further clinical investigation in hematologic malignancies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Bromodomain and extraterminal (BET) protein inhibitors have shown therapeutic potential in preclinical hematologic malignancy models.
- Translating these findings into clinically viable drugs remains a challenge.
Purpose of the Study:
- To elucidate the mechanisms of BET inhibitors in multiple myeloma using the chemical probe I-BET151.
- To evaluate the preclinical efficacy and pharmacologic profile of the novel BET inhibitor I-BET762.
Main Methods:
- Utilized the chemical probe I-BET151 to investigate BET inhibitor mechanisms in multiple myeloma.
- Assessed in vitro and in vivo effects of I-BET151 on cell proliferation and apoptosis.
- Examined the impact of I-BET151 on the expression and chromatin recruitment of MYC and HEXIM1.
- Conducted preclinical studies with I-BET762 in a systemic myeloma xenograft model.
Main Results:
- I-BET151 demonstrated significant antiproliferative and pro-apoptotic effects in multiple myeloma models.
- I-BET151 repressed MYC transcription by inhibiting CDK9 recruitment to chromatin in a BRD2-4-dependent manner.
- I-BET151 induced HEXIM1 upregulation independently of BRD2-4.
- I-BET762 exhibited favorable oral pharmacologic properties and improved survival in a myeloma xenograft model.
Conclusions:
- I-BET151 provides mechanistic insights into BET inhibition in multiple myeloma, highlighting differential regulation of MYC and HEXIM1.
- I-BET762 demonstrates promising preclinical efficacy and pharmacologic characteristics for treating multiple myeloma.
- These findings support the clinical advancement of I-BET762 as a novel therapeutic agent for multiple myeloma.
