GSE109870
transcriptome studies of BRD4 inhibitor BDF-1253 on renal clear carcinoma 786-O cells
As an epigenetic reader, BRD4 is important for the recognition of acetylated lysines and regulation of transcription. As BRD4 regulates the expression of several survival genes, such as c-Myc and Bcl-2, which is vital for the survival of tumor cells, then it is closely involved in various kinds of cancers. Accumulating evidence has proven that BRD4 could serve as a novel anti-cancer pharmaceutical target, and small-molecular BRD4 inhibitors have promising potentials in the treatment of BRD4-related cancers and other diseases. In this study, a novel category of BRD4 inhibitors, which are originated from an approved drug Nitroxoline and its analogues, were synthesized and evaluated by biochemical and cellular assays, as well as the method of crystallography and xenograft mice models. In renal cell carcinoma cell lines, these compounds exhibited efficient inhibition against the expression and protein abundance of BRD4 downstream genes. Moreover, the complex crystal structures of several compounds in this series with the first bromodomain of BRD4 were solved, which revealed the binding mechanism of this novel category of BRD4 inhibitors and facilitated further structural modifications. This series of novel BRD4 inhibitors is promising to become drug candidates for the treatment of renal cell carcinoma after further development and assessments. Overall design: RNA-Seq in renal clear carcinoma cells in the presence or absence of BRD4 inhibitor BDF-1253