Deciphering the Potency of BAY 1238097: A Novel BET Inhibitor Targeting Hematological Tumors

In recent years, a variety of BET inhibitors have demonstrated potent anti-tumor capabilities, with many originating from diazepine and azepine structures, and more recently, quinazolinones and isoxazoles. A new structural framework with significant BET inhibitory properties has been discovered. This study presents the biochemical properties of BAY 1238097, highlighting its anti-proliferative effects on AML and MM cell models.

BAY 1238097 exhibited potent inhibitory effects in vitro, with an IC50 below 100 nM in a TR-FRET assay targeting the BET BRD4 bromodomain and an acetylated histone H4 peptide. The compound showed a preference for BRD4 in NanoBRET assays, with varying IC50 values for BRD4, BRD3, and BRD2. A notable decrease in c-Myc mRNA and protein levels was observed in AML and MM cell lines treated with the compound, and ChIP assays indicated that BAY 1238097 hindered BRD4's binding to c-Myc regulatory regions.

In vivo studies revealed that BAY 1238097 was highly effective in AML models, with T/C values ranging from 13 to 20%. The compound was well tolerated, with minimal body weight loss. It also showed activity in MM models, particularly against a translocated MOLP-8 model, where it was more effective than standard treatments. In another MM model, NCIH929, the compound demonstrated a superior T/C compared to the standard lenalidomide.

Gene expression analysis in rats treated with BAY 1238097 indicated significant impacts on genes related to cell proliferation and immune response.

In conclusion, BAY 1238097 is a strong BET inhibitor that effectively inhibits histone binding and exhibits substantial anti-proliferative activity across various AML and MM models by reducing c-Myc levels and its downstream effects. Clinical trials for BAY 1238097 are anticipated to commence in early 2015.