Abstract B79: BI 894999, a novel BET inhibitor: Treatment of hematological malignancies by repression of super-enhancer driven oncogenes
Authors: Tontsch-Grunt Ulrike , Savarese Fabio , Gerlach Daniel , Gianni Davide , Baum Anke , Scharn Dirk , Engelhardt Harald , Kaya Onur , Schweifer Norbert , Gerstberger Thomas , Kraut Norbert 
Published: May 2016

Background:

Bromodomain and extra-terminal (BET) protein inhibitors comprising the family members BRD2, 3, 4 and T are being extensively studied as treatment options in human haematological malignancies as well as in solid cancers. BRD4 is a key epigenetic regulator playing an important role in activating p-TEFb and governing expression of various oncogenes including MYC by contributing to multi-protein complexes forming so-called super-enhancers. BI 894999 is a novel, potent and selective orally bioavailable inhibitor of the BET family which has recently entered clinical trials.

Results:

Analysis of BI 894999's activity in cell proliferation assays has revealed that it is a highly potent drug, particularly in hematological cell lines (n&gt;40) such as MM, AML and lymphoma. Compound profiling using the BROMOscanTM assay revealed high selectivity for BRD2/3/4 and BRDT. On the cellular level, BI 894999 treatment leads to G1 arrest and subsequent apoptosis. Importantly, the compound also displayed excellent activity (low NM range) on 18/20 primary patient derived AML samples tested ex vivo. Potent tumor growth inhibition of this compound has been demonstrated in disseminated xenograft models of AML (MV-4-11, THP-1) and MM (MOLP-8), and in a transgenic model (Vk*MYC MM) as single agent or in combination with established and investigational therapeutic agents. When comparing the epigenetic regulator BI 894999 to other drugs, active in AML and also targeting chromatin pathways such as histone acetylation or DNA methylation, BI 894999 is found to regulate a very distinct set of genes. As already known, MYC expression and MYC target genes are affected by BET inhibitor treatment, as well as multiple other cancer relevant transcriptional signatures. HEXIM1, a negative regulator of p-TEFb was shown at RNA and protein level to be highly induced by BI 894999 in all cell lines tested so far and was verified as an excellent PD biomarker in extended PK/PD analyses. Detailed molecular analyses employing BRD4 ChIP-seq in MV-4-11 AML cells confirmed the published data that the strong repressive effect of BET inhibition on MYC expression is at least partly mediated by the displacement of BRD4 from a distant 3' MYC super-enhancer region. In addition, we have identified multiple other oncogene driving super-enhancers in AML cells.

Conclusion:

BI 894999 is a potent BET inhibitor which is currently being evaluated in clinical trials. This compound is highly active in MM and AML cell lines and patient samples, as well as in in vivotumor models. HEXIM1 was identified as a robust PD biomarker. Finally, we have demonstrated that BI 894999 is active by antagonizing super-enhancer driven oncogene expression such as MYC.

Citation Format: Ulrike Tontsch-Grunt, Fabio Savarese, Daniel Gerlach, Davide Gianni, Anke Baum, Dirk Scharn, Harald Engelhardt, Onur Kaya, Norbert Schweifer, Thomas Gerstberger, Norbert Kraut. BI 894999, a novel BET inhibitor: Treatment of hematological malignancies by repression of super-enhancer driven oncogenes. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B79.