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BI 894999: A 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.4
About BET proteins
The BET protein family
Bromodomain (BRD) proteins are chromatin ‘readers’; they bind to and interpret post-translational modifications, added by epigenetic ‘writers’ or removed by epigenetic ‘erasers’, and thus, ultimately, regulate gene expression.5,6 BRD4 is a member of the BET family and is considered to be a key epigenetic 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.1,2,6 Pharmacological inhibition of BET proteins has shown therapeutic activity in different models of cancer.2
BI 894999’s mechanism of action
BI 894999 is an oral, potent and selective inhibitor of the BET family of BRD-containing proteins that bind to acetylated histones that induce transcription.5 BI 894999 inhibits BRD4 (as well as BRD2, BRD3 and BRDT) with high selectivity and potency, triggering suppression of target gene transcription (e.g. the oncogene MYC).1‒3
AC, acetyl; BRD4, bromodomain protein 4; CDK9, cyclin-dependent kinase 9; CTD, C-terminal domain; CycT1, cyclin T1; HEXIM1, hexamethylene bisacetamide inducible 1; LARP7, la ribonucleoprotein 7; MEPCE, methylphosphate capping enzyme; mRNA, messenger ribonucleic acid; MYC, myelocytomatosis; P, phosphate; P-TEFb, positive transcription elongation factor; RNAPII, ribonucleic acid polymerase II.
Preclinical and clinical development
In preclinical experiments, BI 894999 has been shown in vitro to be highly active in multiple myeloma (MM) and acute myeloid leukaemia (AML) and patient-derived samples. It has also shown in vivo activity in MM and AML,1,2 as well as activity in small cell lung cancer, prostate and pancreatic tumour models.2
Initial data from a Phase I study (1367.1) reported clinical activity of BI 894999 and determined the safety profile and a maximum tolerated dose for a continuous dosing schedule in solid tumours.3 Investigation of BI 894999 in solid tumours and haematological malignancies is ongoing and recruitment for the Phase I study is in progress.4,7
BET, bromodomain and extra-terminal domain; BOR, best overall response; DCR, disease control rate; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; ORR, objective response rate; PFS, progression-free survival; PK, pharmacokinetics; PSA, prostate-specific antigen.
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. https://clinicaltrials.gov/ct2/show/record/NCT02516553 (Accessed: September 2018).
Zuber J, et al. Nature 2011;478(7370):524–8.
Jung M, et al. Epigenomics 2015;7(3):487–501.
Gerlach D, et al. Oncogene 2018;37(20):2687–701.
*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.
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Last updated: October 2018
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