ConverGene has developed a first-in-class dual-active small molecule inhibitor that i) inhibits BET family of bromodomain-containing proteins, and ii) antagonizes dopamine receptor D2 (DRD2). BET protein family includes BRD4, an epigenetic reader protein that mediates expression of MYC oncogene. Thus, BRD4 is considered as a cancer therapeutic target to indirectly suppress MYC expression. In addition to being a therapeutic target for psychiatric diseases, DRD2 is emerging as a potential therapeutic target in neuroendocrine tumors, subsets of pancreatic ductal adenocarcinoma and small cell lung cancer. Our lead compound showed high activity in a binding test against BRD4 (Ki = 34 nM); exhibited high bioavailability upon oral administration; profoundly suppressed MYC expression both in vitro and in vivo; inhibited growth of AML and solid tumor cells in xenograft models; potently inhibited both isoforms of DRD2 (IC50 0.1 µM); and interfered with DRD2/β-arrestin/Akt pathway in vitro. Therefore, our BRD4/DRD2 dual-active compounds may hold promise as a novel class of therapeutics that interferes with both cancer growth and maintenance by simultaneously interfering with MYC and DRD2 pathways. We currently are investigating these dual-active compounds in multiple in vitro and in vivo models and expect to report the outcomes at the AACR Annual Meeting in 2017.

Citation Format: Makoto Yoshioka, Jay Chauhan, Steven Fletcher, Jeffrey W. Strovel. Development of a first in class inhibitor of BET bromodomains and dopamine receptor 2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5062. doi:10.1158/1538-7445.AM2017-5062