Physachenolide C is a Potent, Selective BET Inhibitor

J Med Chem. 2023 Jan 12;66(1):913-933. doi: 10.1021/acs.jmedchem.2c01770. Epub 2022 Dec 28.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins
  • Humans
  • Male
  • Nuclear Proteins
  • Protein Domains
  • Transcription Factors*
  • Withanolides*

Substances

  • Transcription Factors
  • physachenolide C
  • Withanolides
  • Nuclear Proteins
  • Cell Cycle Proteins
  • BRD4 protein, human