Potent anti-myeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762
Menée in vitro et in vivo sur des modèles de myélome multiple, cette étude évalue l'activité antitumorale de deux composés appelés I-BET151 et I-BET762, des inhibiteurs de BET
The bromodomain and extra terminal (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 disclosed. Herein we expand the mechanistic understanding of BET inhibitors in multiple myeloma using the chemical probe molecule I-BET151. I-BET151 induces apoptosis and exerts strong anti-proliferative 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 programmes, by abrogating recruitment to chromatin of the P-TEFb component CDK9, in a BRD2-4-dependent manner. In contrast, transcriptional upregulation of HEXIM1 is BRD2-4 independent. Finally, pre-clinical studies show that I-BET762 has favourable pharmacological profile as an oral agent and inhibited 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 anti-myeloma agent I-BET762 and reveal insights into biological pathways required for myeloma cell proliferation.