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 - Publisher Copyright: © 2023 American Chemical Society. All rights reserved.
PY - 2023/1/12
Y1 - 2023/1/12
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
SN - 0022-2623
VL - 66
SP - 913
EP - 933
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 1
ER -