TY - JOUR
T1 - Physachenolide C is a Potent, Selective BET Inhibitor
AU - Zerio, Christopher J.
AU - Sivinski, Jared
AU - Wijeratne, E. M.Kithsiri
AU - Xu, Ya Ming
AU - Ngo, Duc T.
AU - Ambrose, Andrew J.
AU - Villa-Celis, Luis
AU - Ghadirian, Niloofar
AU - Clarkson, Michael W.
AU - Zhang, Donna D.
AU - Horton, Nancy C.
AU - Gunatilaka, A. A.Leslie
AU - Fromme, Raimund
AU - Chapman, Eli
N1 - Funding Information:
C.J.Z., J.S., and A.J.A. are funded by T32 GM008804. DDZ is supported by National Institutes of Health grant R35ES031575. This work was supported in part by a grant from the Arizona Biomedical Research Center (grant number ADHS-16-162515). 22Rv1 cells were kindly provided by Dr. Len Neckers (NCI, Bethesda, MD, USA). We would like to acknowledge Dr. May Khanna for graciously allowing us to use her AlphaScreen assay reader. We would also like to thank Ms. Manping X. Liu for some cytotoxicity assay data and Dr. Qin M. Chen for graciously allowing us to use her Microscale Thermophoresis instrument.
Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.2c01770
DO - 10.1021/acs.jmedchem.2c01770
M3 - Article
C2 - 36577036
AN - SCOPUS:85145456092
SN - 0022-2623
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
ER -