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Physachenolide C is a Potent, Selective BET Inhibitor.

Christopher J Zerio¹, Jared Sivinski¹, E M Kithsiri Wijeratne²

¹College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel Street, PO Box 210207, Tucson, Arizona 85721, United States.

Journal of Medicinal Chemistry

|December 28, 2022

Summary

This summary is machine-generated.

Physachenolide C (PCC), a natural product, inhibits bromodomain and extra-terminal domain (BET) proteins, showing potent anti-cancer effects in prostate cancer cells by promoting BET protein degradation.

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Area of Science:

Chemical Biology
Molecular Oncology
Natural Products Chemistry

Background:

Bromodomain and extra-terminal domain (BET) proteins (BRD2, BRD3, BRD4) are epigenetic readers regulating gene transcription.
Dysregulation of BET proteins is implicated in various cancers, including prostate cancer (PC).
Natural products offer a rich source for novel therapeutic agents targeting cancer pathways.

Purpose of the Study:

To identify cellular targets of the natural product physachenolide C (PCC).
To characterize the inhibitory mechanism of PCC against BET proteins.
To evaluate the anti-cancer efficacy of PCC in prostate cancer models.

Main Methods:

Biotinylated pulldown assays to identify protein interactors.
BROMOscan bromodomain profiling and biochemical assays.
X-ray crystallography and NMR spectroscopy for structural analysis.
Cytotoxicity assays in prostate cancer cell lines.

Main Results:

PCC identified BET proteins (BRD2, BRD3, BRD4) as potential cellular targets.
PCC acts as a BET inhibitor with selectivity for bromodomain (BD)-1 of BRD3 and BRD4.
Structural studies revealed specific interactions underlying PCC's potency and selectivity.
PCC functions as a molecular glue, inducing proteasome-mediated degradation of BRD3 and BRD4.
PCC demonstrated superior cytotoxicity compared to (+)-JQ1 in diverse prostate cancer cell lines.

Conclusions:

PCC is a potent BET inhibitor and molecular glue targeting BRD3 and BRD4.
PCC exhibits significant anti-cancer activity in prostate cancer cells, independent of AR signaling.
PCC represents a promising therapeutic lead for prostate cancer treatment.