Abstract B112: Development and preclinical evaluation of a novel BET inhibitor FF-1027T

Abstract

Abstract Bromodomain and extra-terminal (BET) family of proteins regulate gene expression by binding acetylated-lysine residue in histone at the gene promoter and enhancer elements through the two bromodomains (BD1 and BD2). Subsequently, they activate transcriptional elongation at the binding sites. Small-molecule compounds inhibiting the interaction between BET proteins and acetylate-lysine in histone have been expected as a promising strategy for cancer therapy. They can show pharmacologic action by regulating the transcription of MYC and other cancer-associated genes. We identified a novel BET inhibitor, FF-1027T, that is structurally different from the (+)JQ-1 class BET inhibitors such as OTX015. FF-1027T is more soluble in aqueous solution than known BET inhibitors, which offers an advantage in the application of drug formulations. Through the TR-FRET assay, FF-1027T exhibited binding to BRD2/3/4 with a preference for BD1 over BD2. FF-1027T showed antiproliferative activity in vitro across broad cancer cell lines derived from hematologic malignancies or solid tumors. In accordance with the previous report about BET inhibitors, FF-1027T displayed higher antiproliferative activity to hematologic malignancies than solid tumor-derived cell lines with less than 100 nM GI50 values (12 out of 21 cells lines). In particular, FF-1027T showed anti-proliferative activities against cell lines derived from solid tumors, such as colon, lung, breast, and prostate cancer, with less than 300 nM GI50 values in almost 30% of the cell lines. In AML xenograft tumor models, oral or intravenous administration of FF-1027T resulted in almost complete reduction of tumor growth. Intravenous treatment was achieved by high solubility in an aqueous solution of FF-1027T. Our present results suggested that gastrointestinal tract (GI) damage through topical effects of BET inhibitors on the mucosal surface can be avoided by intravenous administration. These results demonstrated that FF-1027T is a potent BET inhibitor and supports the clinical further development of FF-1027T in hematologic malignancies and solid tumors. Citation Format: Keiko Makita, Kazunori Saeki, Tadashi Tanaka, Yasutomo Kawanishi, Toshifumi Kimura, Shinichi Watanabe, Chihaya Kakinuma, Shinji Hagiwara, Yasuhiro Shimada. Development and preclinical evaluation of a novel BET inhibitor FF-1027T [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B112.