Stanford Advisors

Contact

  • Academic
    sordone@stanford.edu
    University - Scholar Department: Chemistry Position: Postdoctoral Scholar

Additional Info

Lab Affiliations

All Publications

  • Rational Design and Development of Selective BRD7 Bromodomain Inhibitors and Their Activity in Prostate Cancer JOURNAL OF MEDICINAL CHEMISTRY Ordonez-Rubiano, S. C., Maschinot, C. A., Wang, S., Sood, S., Baracaldo-Lancheros, L. F., Strohmier, B. P., McQuade, A. J., Smith, B. C., Dykhuizen, E. C. 2023; 66 (16): 11250-11270

    Abstract

    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.

    View details for DOI 10.1021/acs.jmedchem.3c00671

    View details for Web of Science ID 001044532300001

    View details for PubMedID 37552884

    View details for PubMedCentralID PMC10641717

https://orcid.org/0000-0001-7967-5024