Physachenolide C is a Potent, Selective BET Inhibitor

Christopher J. Zerio; Jared Sivinski; E. M.Kithsiri Wijeratne; Ya Ming Xu; Duc T. Ngo; Andrew J. Ambrose; Luis Villa-Celis; Niloofar Ghadirian; Michael W. Clarkson; Donna D. Zhang; Nancy C. Horton; A. A.Leslie Gunatilaka; Raimund Fromme; Eli Chapman

doi:10.1021/acs.jmedchem.2c01770

Physachenolide C is a Potent, Selective BET Inhibitor

Christopher J. Zerio, Jared Sivinski, E. M.Kithsiri Wijeratne, Ya Ming Xu, Duc T. Ngo, Andrew J. Ambrose, Luis Villa-Celis, Niloofar Ghadirian, Michael W. Clarkson, Donna D. Zhang, Nancy C. Horton, A. A.Leslie Gunatilaka, Raimund Fromme, Eli Chapman

Molecular Sciences, School of (SMS)

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English (US)
Pages (from-to)	913-933
Number of pages	21
Journal	Journal of Medicinal Chemistry
Volume	66
Issue number	1
DOIs	https://doi.org/10.1021/acs.jmedchem.2c01770
State	Published - Jan 12 2023

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.2c01770

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@article{859b1d83ebbf4e478b48fbe46856ad3e,

title = "Physachenolide C is a Potent, Selective BET Inhibitor",

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.",

author = "Zerio, {Christopher J.} and Jared Sivinski and Wijeratne, {E. M.Kithsiri} and Xu, {Ya Ming} and Ngo, {Duc T.} and Ambrose, {Andrew J.} and Luis Villa-Celis and Niloofar Ghadirian and Clarkson, {Michael W.} and Zhang, {Donna D.} and Horton, {Nancy C.} and Gunatilaka, {A. A.Leslie} and Raimund Fromme and Eli Chapman",

year = "2023",

month = jan,

day = "12",

doi = "10.1021/acs.jmedchem.2c01770",

language = "English (US)",

volume = "66",

pages = "913--933",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

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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

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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Physachenolide C is a Potent, Selective BET Inhibitor

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Physachenolide C with Bromodomain (BRD3-BD1)

BD2 domain of human BRD3 bound to Physachenolide C

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Physachenolide C is a Potent, Selective BET Inhibitor

Abstract

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Datasets

Physachenolide C with Bromodomain (BRD3-BD1)

BD2 domain of human BRD3 bound to Physachenolide C

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