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BI 894999: A selective inhibitor of the BET family
BI 894999* is an oral, potent and selective inhibitor of the bromodomain and extra-terminal (BET) family of bromodomain (BDR)-containing proteins.1–3 It is currently being investigated in a Phase I clinical trial in patients with advanced solid tumours.4
About BET proteins
BRD proteins are chromatin ‘readers’. They bind to and interpret post-translational modifications added by epigenetic ‘writers’ or removed by epigenetic ‘erasers’ and thereby regulate gene expression.5,6
BRD4 is a member of the BET family and is considered to be a key epigenetic regulator.1,2 It controls a subset of genes by recognising key regulatory elements and indirectly modulating essential transcription factors, such as c-Myc and E2F.5 BRD4 deregulation is implicated in a number of haematological malignancies and solid tumours.6–11
BI 894999’s mechanism of action
BI 894999 is an oral inhibitor of the BET family of BRD-containing proteins that bind to acetylated histones inducing transcription.1–3,12
BI 894999 inhibits BRD4 (as well as BRD2, BRD3 and BRDT) with high selectivity and potency, 1–3,12 triggering suppression of target gene transcription (e.g. the oncogene Myc). 5,6,13
BI 894999’s mechanism of action
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
BI 894999 has shown high in vitro and in vivo activity in multiple myeloma, acute myeloid leukaemia and solid tumours.1–3
Initial data from a Phase I study (1367.1) of BI 894999 demonstrated clinical activity and a manageable safety profile in patients with solid tumours.3 It also established the maximum tolerated dose for continuous dosing.3 Further investigations of BI 894999 are now underway in patients with advanced, unresectable and/or metastatic solid tumours that have failed on, or are unsuitable for, conventional treatment.4
BET, bromodomain and extra-terminal domain; BOR, best overall response; CR, complete reponse; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; ORR, objective response; PFS, progression-free survival; PK, pharmacokinetics; PR, partial response; 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. 15):11574.
Aftimos PG, et al. J Clin Oncol 2017;35(Suppl. 15):2504.
ClinicalTrials.gov. NCT02516553. https://clinicaltrials.gov/ct2/show/record/NCT02516553 (Accessed: April 2019).
Jung M, et al. Epigenomics 2015;7(3):487–501.
Zuber J, et al. Nature 2011;478(7370):524–8.
Fu LL, et al. Oncotarget 2015;6:5501–16.
Xu Y, Vakoc CR. Cold Spring Harb Perspect Med 2017;7:pii: a026674.
Filippakopoulos P, et al. Nature 2010;468:1067–73.
Delmore JE, et al. Cell 2011;146:904–17.
Shi J, Vakoc C. Molecular Cell 2014;54:728–36; 6.
Doroshow DB, et al. Ann Oncol 2017;28:1776–87.
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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Page last updated: May 2019
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