Physachenolide C is a Potent, Selective BET Inhibitor

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.