Abstract
A pulldown using a biotinylated natural product of interest in the 17β-hydroxywithanolide (17-BHW) class, physachenolide C (PCC), identified the bromodomain and extra-terminal domain (BET) family of proteins (BRD2, BRD3, and BRD4), readers of acetyl-lysine modifications and regulators of gene transcription, as potential cellular targets. BROMOscan bromodomain profiling and biochemical assays support PCC as a BET inhibitor with increased selectivity for bromodomain (BD)-1 of BRD3 and BRD4, and X-ray crystallography and NMR studies uncovered specific contacts that underlie the potency and selectivity of PCC toward BRD3-BD1 over BRD3-BD2. PCC also displays characteristics of a molecular glue, facilitating proteasome-mediated degradation of BRD3 and BRD4. Finally, PCC is more potent than other withanolide analogues and gold-standard pan-BET inhibitor (+)-JQ1 in cytotoxicity assays across five prostate cancer (PC) cell lines regardless of androgen receptor (AR)-signaling status.
Original language | English (US) |
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Pages (from-to) | 913-933 |
Number of pages | 21 |
Journal | Journal of Medicinal Chemistry |
Volume | 66 |
Issue number | 1 |
DOIs | |
State | Published - Jan 12 2023 |
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
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Dive into the research topics of 'Physachenolide C is a Potent, Selective BET Inhibitor'. Together they form a unique fingerprint.Datasets
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Physachenolide C with Bromodomain (BRD3-BD1)
Zerio, C. J. (Contributor), Sivinski, J. (Contributor), Wijeratne, E. M. K. (Contributor), Xu, Y.-M. (Contributor), Ngo, D. T. (Contributor), Ambrose, A. J. (Contributor), Villa-Celis, L. (Contributor), Ghadirian, N. (Contributor), Clarkson, M. W. (Contributor), Zhang, D. D. (Contributor), Horton, N. C. (Contributor), Gunatilaka, A. A. L. (Contributor), Fromme, R. (Contributor) & Chapman, E. (Contributor), Protein Data Bank (PDB), Sep 21 2022
DOI: 10.2210/pdb7R8R/pdb, https://www.wwpdb.org/pdb?id=pdb_00007r8r
Dataset
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BD2 domain of human BRD3 bound to Physachenolide C
Zerio, C. J. (Contributor), Sivinski, J. (Contributor), Wijeratne, E. M. K. (Contributor), Xu, Y.-M. (Contributor), Ngo, D. T. (Contributor), Ambrose, A. J. (Contributor), Villa-Celis, L. (Contributor), Ghadirian, N. (Contributor), Clarkson, M. W. (Contributor), Zhang, D. D. (Contributor), Horton, N. C. (Contributor), Gunatilaka, A. A. L. (Contributor), Fromme, R. (Contributor) & Chapman, E. (Contributor), Protein Data Bank (PDB), Jan 11 2023
DOI: 10.2210/pdb7S3P/pdb, https://www.wwpdb.org/pdb?id=pdb_00007s3p
Dataset