2. Academic Validation
  3. Physachenolide C is a Potent, Selective BET Inhibitor

Physachenolide C is a Potent, Selective BET Inhibitor

  • J Med Chem. 2023 Jan 12;66(1):913-933. doi: 10.1021/acs.jmedchem.2c01770.
Christopher J Zerio 1,  Jared Sivinski 1,  E M Kithsiri Wijeratne 2,  Ya-Ming Xu 2,  Duc T Ngo 1,  Andrew J Ambrose 1,  Luis Villa-Celis 1,  Niloofar Ghadirian 3,  Michael W Clarkson 4,  Donna D Zhang 1,  Nancy C Horton 3,  A A Leslie Gunatilaka 2,  Raimund Fromme 5,  Eli Chapman 1
Affiliations

Affiliations

  • 1 College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel Street, PO Box 210207, Tucson, Arizona 85721, United States.
  • 2 College of Agriculture and Life Sciences, School of Natural Resources and the Environment, Southwest Center for Natural Products Research, University of Arizona, 250 E. Valencia Road, Tucson, Arizona 85706, United States.
  • 3 Department of Molecular and Cellular Biology, University of Arizona, 1007 E. Lowell Street, Tucson, Arizona 85721, United States.
  • 4 Department of Chemistry and Biochemistry, University of Arizona, 1041 E. Lowell Street, Tucson, Arizona 85719, United States.
  • 5 School of Molecular Sciences, Biodesign Institute, Arizona State University, 1001 S. McAllister Avenue, Tempe, Arizona 85287, United States.
PMID: 36577036 DOI: 10.1021/acs.jmedchem.2c01770
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.

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