Rational Design and Development of Selective BRD7 Bromodomain Inhibitors and Their Activity in Prostate Cancer. J Med Chem 2023 Aug 24;66(16):11250-11270
Date
08/08/2023Pubmed ID
37552884Pubmed Central ID
PMC10641717DOI
10.1021/acs.jmedchem.3c00671Scopus ID
2-s2.0-85168344957 (requires institutional sign-in at Scopus site) 1 CitationAbstract
Bromodomain-containing proteins are readers of acetylated lysine and play important roles in cancer. Bromodomain-containing protein 7 (BRD7) is implicated in multiple malignancies; however, there are no selective chemical probes to study its function in disease. Using crystal structures of BRD7 and BRD9 bromodomains (BDs) bound to BRD9-selective ligands, we identified a binding pocket exclusive to BRD7. We synthesized a series of ligands designed to occupy this binding region and identified two inhibitors with increased selectivity toward BRD7, 1-78 and 2-77, which bind with submicromolar affinity to the BRD7 BD. Our binding mode analyses indicate that these ligands occupy a uniquely accessible binding cleft in BRD7 and maintain key interactions with the asparagine and tyrosine residues critical for acetylated lysine binding. Finally, we validated the utility and selectivity of the compounds in cell-based models of prostate cancer.
Author List
Ordonez-Rubiano SC, Maschinot CA, Wang S, Sood S, Baracaldo-Lancheros LF, Strohmier BP, McQuade AJ, Smith BC, Dykhuizen ECAuthor
Brian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Chromosomal Proteins, Non-HistoneHumans
Ligands
Lysine
Male
Prostatic Neoplasms
Transcription Factors
