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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.