Alobresib is an Orally Active BET Bromodomain Inhibitor for Uterine Serous Carcinoma Treatment
Posted On 2019-07-31
Uterine serous carcinoma is a rare and highly aggressive variant of endometrial cancer. Uterine serous carcinoma accounts for 10% of all endometrial cancer; however, it carries the poorest prognosis, with 5-year survival rates as low as 55%. Whole-exome sequencing studies have recently reported c-Myc gene amplification in a large number of uterine serous carcinomas, suggesting c-Myc as a potential therapeutic target. The c-Myc oncogene is overexpressed in the majority of human cancers and contributes to the cause of at least 40% of tumors. c-Myc overexpression results in coordinated changes in level of expression of gene families which result in increased cellular proliferation. On the other hand, c-Myc overexpression may also occur as a result of post-translational modifications.
In this study, Elena Bonazzoli, et al characterized a BET bromodomain inhibitor Alobresib (GS-5829). Alobresib reversibly binds the BET bromodomain proteins BRD2, BRD3, BRD4, and BRDT and prevents protein–protein interaction between BET proteins and acetylated histones and transcription factors, against multiple primary USC cell lines overexpressing c-Myc. BET proteins, especially BRD4, have attracted interest as candidate therapeutic targets due to their putative involvement in the pathogenesis of various diseases, including cancer and inflammatory diseases. Researchers investigate the activity Alobresib against primary USC cultures and USC xenografts.
Alobresib inhibits cell proliferation in primary uterine serous carcinoma cell lines. In addition, Alobresib exhibits excellent oral bioavailability after a single administration in animals bearing USC-ARK2 tumors. Alobresib impaires USC-ARK and USC-ARK2 xenograft tumor growth in vivo. Alobresib significantly reduces c-Myc protein expression in ARK2 xenograft tumor samples. In conclusion, results demonstrate remarkable activity of Alobresib both in vitro as well as in vivo.
Bonazzoli E, et al. Inhibition of BET Bromodomain Proteins with GS-5829 and GS-626510 in Uterine Serous Carcinoma, a Biologically Aggressive Variant of Endometrial Cancer. Clin Cancer Res. 2018 Oct 1;24(19):4845-4853.