Abstract 3524: BAY 1238097, a novel BET inhibitor with strong efficacy in hematological tumor models

Several BET inhibitors with strong anti-tumor efficacy have been described in the last few years. Most of them are derived from diazepine and azepine scaffolds, but more recently quinazolinones and isoxazoles chemotypes have also been described. We have identified a novel scaffold with strong BET inhibitory activity. Here we describe the biochemical characteristics of BAY 1238097 and its anti-proliferative activity in acute myeloid leukemia (AML) and multiple myeloma (MM) models. In vitro, BAY 1238097 showed strong inhibitory activity (IC50 In vivo, BAY 1238097 showed strong efficacy in the AML models THP-1, MOLM-13 and KG-1, with T/C between 13 and 20%. Overall, the compound was well tolerated at MTD, with body weight losses of 5-9% at nadir. BAY 1238097 was also active in MM models. Efficacy was observed against a human IGH-cyclin D1 translocated MOLP-8 model with a T/C of 3%, whereas the standard-of-care agents bortezomib and lenalidomide were inactive or poorly active. In this model, BAY 1238097 was well tolerated at 10 mg/kg applied over 14 days, with no body weight loss measured. BAY 1238097 was also active against the FGFR/MMSET translocated model NCIH929, with 19% T/C versus 49% T/C for the standard-of-care lenalidomide. The compound was well tolerated applied at 12 mg/kg for 9 days (maximum body weight loss 6%). Gene expression profiling performed in liver, blood and duodenum of rats treated daily with 2 mg/kg BAY 1238097 for 14 days demonstrated substantial effects on genes involved in cell proliferation and in the immune response in vivo. Altogether, BAY 1238097 is a potent inhibitor of BET binding to histones and has strong anti-proliferative activity in different AML and MM models through down-regulation of c-Myc levels and its downstream transcriptome. Initiation of clinical studies with BAY 1238097 is planned for early 2015. Citation Format: Pascale Lejeune, Tatsuo Sugawara, Kathy A. Gelato, Heidrun Ellinger-Ziegelbauer, Amaury E. Fernandez-Montalvan, Norbert Schmees, Stephan Siegel, Hilmar Weinmann, Volker Gekeler, Annette O. Walter, Matthias Ocker, Stuart Ince, Bernard Haendler. BAY 1238097, a novel BET inhibitor with strong efficacy in hematological tumor models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3524. doi:10.1158/1538-7445.AM2015-3524