Targeting Super-Enhancer-Driven Oncogenes: The Therapeutic Potential of BI 894999 in Hematological Malignancies

The study focuses on the development and evaluation of BI 894999, a novel BET protein inhibitor targeting BRD2, 3, 4, and T proteins. It is a potent, selective, and orally bioavailable drug that has entered clinical trials as a potential treatment for various cancers, particularly hematological malignancies and solid tumors.

In vitro testing has shown BI 894999 to be highly effective, especially against hematological cell lines such as multiple myeloma (MM), acute myeloid leukemia (AML), and lymphoma. The drug demonstrates high selectivity for its targets and induces cell cycle arrest and apoptosis. It also exhibits significant activity against primary AML patient samples and inhibits tumor growth in xenograft models of AML and MM.

Compared to other epigenetic drugs that target chromatin pathways, BI 894999 regulates a distinct set of genes. It affects MYC expression and its target genes, as well as other cancer-relevant transcriptional signatures. The study identified HEXIM1, which inhibits p-TEFb, as a biomarker that is highly induced by BI 894999 and can be used for pharmacodynamic analysis.

Molecular studies using BRD4 ChIP-seq in AML cells confirmed that the inhibitor's repression of MYC expression is mediated by the displacement of BRD4 from the 3' MYC super-enhancer region. Additionally, other oncogene-driving super-enhancers in AML cells were discovered.

In conclusion, BI 894999 is a promising BET inhibitor under clinical investigation, showing high activity against MM and AML cell lines, patient samples, and in vivo tumor models. HEXIM1 serves as a reliable pharmacodynamic biomarker, and the compound's mechanism of action involves the antagonism of super-enhancer-driven oncogene expression, such as MYC.