BRD9 is a subunit of the human BAF (SWI/SNF) nucleosome remodeling complex. Besides, BRD9 contains a bromodomain and is closely related to BRD7. Importantly, The BRD9 gene is frequently present in variable copy numbers in lung cancer and has emerged as an attractive therapeutic target in cancer. Moreover, the study shows that inhibit bromodomain and the extra-terminal domain (BET) subfamily have availed new therapeutic opportunities in cancer.
PROTAC (proteolysis targeting chimera) consists of two covalently linked protein-binding molecules: one capable of engaging an E3 ubiquitin ligase, and another that binds to a target protein meant for degradation. Besides, the Recruitment of the E3 ligase to the target protein results in ubiquitination and subsequent degradation of the target protein via the proteasome.
In this article, we will introduce a PROTAC that can selectively degrade BRD9, dBRD9.
dBRD9 is a PEG-linked pomalidomide conjugate, was found to prompt rapid BRD9 degradation over a broad range of concentrations. Besides, also shows an improved bromodomain engagement profile, with reduced binding activity across the BET family. Meanwhile, dBRD9 (0.5, 5, 50, 500, 5000 nM; 4 h) decreases the expression of BRD9 protein in MOLM-13 cells dose-dependent. But shows no significant effect on the expression of BRD4 and BRD7 proteins. Moreover, dBRD9 (100 nM; 2 h) shows selectivity for BRD9 degradation with a 5.5 median fold lower abundance in dBRD9 treated samples in MOLM-13 cells. But the levels of other proteins were remarkably static between treatments with 99% of proteins differing less than 0.30 fold. In addition, dBRD9 (0-100; 7 days) shows a potent anti-proliferative effect in EOL-1 and MOML-13 cells in a dose-dependent manner.
All in all, dBRD9 is a PROTAC and can selective degrades BRD9.