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Selective inhibitor of the BET Family
BI 894999* is an oral, highly potent and selective inhibitor of bromodomain and extra-terminal motif (BET)-containing proteins.1–3 A Phase I clinical trial evaluating BI 894999 in patients with advanced malignancies is currently being conducted.
About BI 894999
The BET protein family
Bromodomain (BRD) proteins are chromatin ‘readers’; they bind to and interpret posttranslational modifications, added by epigenetic ‘writers’ or removed by epigenetic ‘erasers’ and thus ultimately regulate gene expression. BRD4 is a member of the bromodomain and extra terminal domain protein (BET) family and is considered to be a general transcriptional regulator. Inhibition of BRD4 can exert a selective effect on the expression of a small number of genes in specific cells. A high level of BRD4 occupancy at certain enhancer elements, termed ‘super-enhancers’, renders target genes particularly sensitive to BET inhibition.1-2 Pharmacological inhibition of BET proteins has shown therapeutic activity in different models of cancer.
BI 894999’s mechanism of action
BI 894999 is an oral, highly potent and selective inhibitor of the BET family. BRD4 inhibition through BI 894999 triggers suppression of the transcription of BRD4 target genes.
Preclinical and clinical development
In preclinical experiments BI 894999 has been shown in vitro to be highly active in multiple myeloma (MM), acute myeloid leukaemia (AML) and non-Hodgkin lymphoma (NHL) cell lines and patient derived samples. It has also shown in vivo activity in MM, AML and NHL tumour models1,2 as well as potency in small cell lung cancer, prostate and pancreas tumour models.2
Initial data from a Phase I study (1367.1) determined the safety profile and a maximum tolerated dose for a continuous dosing schedule in solid tumours; signs of clinical activity were reported in phase I.3 Investigation of BI 894999 in haematological malignancies and solid tumours is ongoing and recruitment for the phase I study is in progress.3,4
DCR, disease control rate; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; ORR, objective response rate; PFS, progression-free survival; PK, pharmacokinetics.
Tontsch-Grunt U, et al. Poster presented at AACR-NCI-EORTC 2015; Abstract B79.
Tontsch-Grunt U, et al. J Clin Oncol 2016;34(Suppl.): Abstract 11574.
Aftimos PG, et al. J Clin Oncol 2017;35(Suppl.): Abstract 2504.
ClinicalTrials.gov. NCT02516553. Available at: https://clinicaltrials.gov/ct2/show/record/NCT02516553. Accessed: July 2017.
*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.
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