Abstract 1231: Identification of selective Brd4 degrader for cancer treatment

Abstract

Abstract Human BET family proteins consist of four members, termed Brd2, Brd3, Brd4 and testis-specific BrdT. They all contain two highly conserved tandem N-terminal bromodomains (BD1 and BD2) and a C-terminal extra-terminal (ET) domain. One of the major functions of the BET proteins is to recognize the acetylated lysine residues on histone proteins and transcriptional factors, thereby regulating the gene expression. Recent studies have implicated the BET proteins as a valid pharmaceutical target for treating cancers. Disrupting the interactions by pan-BET inhibitors have displayed beneficial prognosis in both the preclinical animal models and the clinic trials. Nevertheless, dose limiting adverse effects including mild to moderate gastrointestinal toxicity and fatigue, as well as reversible grade 3 thrombocytopenia, have been observed for some pan-BET inhibitors clinically. While the three BET proteins BRD2, BRD3 and BRD4 exhibit redundant and dynamic patterns in regulating gene transcription, the individual protein may have distinct functions. Thus developing of isoform-selective regulatory reagents is of interest to elucidate the biological function of the BET proteins and their applications in pharmaceutical development. Here, we describe our efforts for the development of selective Brd4 degraders with proteolysis-targeting chimera approaches. Our medicinal chemistry campaign led to the discovery of a series of highly potent Brd4 selective degraders. Treat the tumor cells with these selective Brd4 degraders resulted in rapid, sustained and selective degradation of Brd4. RNA-seq and real time RT-PCR analysis indicates the selective Brd4 degrader exhibits distinct regulation of gene expression in tumor cells comparing to pan-BET degraders and inhibitors. Further tests with flow cytometry analysis and WST-8 assays indicates that selective Brd4 degraders strongly suppress the tumor cells growth and induces the cell death through induction of apoptosis. Strong tumor suppression was also observed with treatment of selective Brd4 degrader in mouse xenograft models. These results suggest that the selective Brd4 degraders are strong candidates for potential tumor treatment. Citation Format: Biao Hu, Jiantao Hu, fuming Xu, Liyue Huang, Mi Wang, Shaomeng Wang. Identification of selective Brd4 degrader for cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1231.