Small-molecule disruption of androgen receptor–dependent chromatin clusters

Sarah E. Kohrt; Emily J. Novak; Subhashish Tapadar; Bocheng Wu; Jonathan Strope; Yaw Asante; Hyunmin Kim; Matthew S. Chang; Douglas Gurdak; Athar Khalil; Michael Rood; Eric Raftery; Diana Stavreva; Holly M. Nguyen; Lisha G. Brown; Maddy Ramser; Cody Peer; Warren M. Meyers; Nicholas Aboreden; Maharshi Chakravortee; Richard Sallari; Peter S. Nelson; Kathleen K. Kelly; Thomas G.W. Graham; Xavier Darzacq; William D. Figg; Adegboyega K. Oyelere; Eva Corey; Remi Adelaiye-Ogala; Berkley E. Gryder

doi:10.1073/pnas.2406239121

Small-molecule disruption of androgen receptor–dependent chromatin clusters

Sarah E. Kohrt, Emily J. Novak, Subhashish Tapadar, Bocheng Wu, Jonathan Strope, Yaw Asante, Hyunmin Kim, Matthew S. Chang, Douglas Gurdak, Athar Khalil, Michael Rood, Eric Raftery, Diana Stavreva, Holly M. Nguyen, Lisha G. Brown, Maddy Ramser, Cody Peer, Warren M. Meyers, Nicholas Aboreden, Maharshi ChakravorteeRichard Sallari, Peter S. Nelson, Kathleen K. Kelly, Thomas G.W. Graham, Xavier Darzacq, William D. Figg, Adegboyega K. Oyelere^*, Eva Corey^*, Remi Adelaiye-Ogala^*, Berkley E. Gryder^*

^*Corresponding author for this work

Surgery

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

Abstract

Sustained androgen receptor (AR) signaling during relapse is a central driver of metastatic castration-resistant prostate cancer (mCRPC). Current AR antagonists, such as enzalutamide, fail to provide long-term benefit for the mCRPC patients who have dramatic increases in AR expression. Here, we report AR antagonists with efficacy in AR-overexpressing models. These molecules bind to the ligand-binding domain of the AR, promote AR localization to the nucleus, yet potently and selectively down-regulate AR-target genes. The molecules BG-15a and the pharmacokinetically optimized BG-15n elicit a decrease in cell and tumor growth in vitro and in vivo in models of mCRPC. BG-15a/n treatment causes the collapse of chromatin loops between enhancers and promoters at key genes in the AR-driven epigenome. AR binding in the promoter, as well as 3D chromatin clustering, is needed for genes to respond. BG-15a/n represent promising agents for treating patients with relapsed AR-driven mCRPC tumors.

Original language	English
Article number	e2406239121
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	121
Issue number	48
DOIs	https://doi.org/10.1073/pnas.2406239121
State	Published - 26 Nov 2024

Keywords

androgen receptor
chromatin architecture
epigenetics
gene regulation
prostate cancer

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10.1073/pnas.2406239121

Cite this

Kohrt, S. E., Novak, E. J., Tapadar, S., Wu, B., Strope, J., Asante, Y., Kim, H., Chang, M. S., Gurdak, D., Khalil, A., Rood, M., Raftery, E., Stavreva, D., Nguyen, H. M., Brown, L. G., Ramser, M., Peer, C., Meyers, W. M., Aboreden, N., ... Gryder, B. E. (2024). Small-molecule disruption of androgen receptor–dependent chromatin clusters. Proceedings of the National Academy of Sciences of the United States of America, 121(48), Article e2406239121. https://doi.org/10.1073/pnas.2406239121

@article{047dbd3e4c0f4949b80b9475b599e435,

title = "Small-molecule disruption of androgen receptor–dependent chromatin clusters",

abstract = "Sustained androgen receptor (AR) signaling during relapse is a central driver of metastatic castration-resistant prostate cancer (mCRPC). Current AR antagonists, such as enzalutamide, fail to provide long-term benefit for the mCRPC patients who have dramatic increases in AR expression. Here, we report AR antagonists with efficacy in AR-overexpressing models. These molecules bind to the ligand-binding domain of the AR, promote AR localization to the nucleus, yet potently and selectively down-regulate AR-target genes. The molecules BG-15a and the pharmacokinetically optimized BG-15n elicit a decrease in cell and tumor growth in vitro and in vivo in models of mCRPC. BG-15a/n treatment causes the collapse of chromatin loops between enhancers and promoters at key genes in the AR-driven epigenome. AR binding in the promoter, as well as 3D chromatin clustering, is needed for genes to respond. BG-15a/n represent promising agents for treating patients with relapsed AR-driven mCRPC tumors.",

keywords = "androgen receptor, chromatin architecture, epigenetics, gene regulation, prostate cancer",

author = "Kohrt, {Sarah E.} and Novak, {Emily J.} and Subhashish Tapadar and Bocheng Wu and Jonathan Strope and Yaw Asante and Hyunmin Kim and Chang, {Matthew S.} and Douglas Gurdak and Athar Khalil and Michael Rood and Eric Raftery and Diana Stavreva and Nguyen, {Holly M.} and Brown, {Lisha G.} and Maddy Ramser and Cody Peer and Meyers, {Warren M.} and Nicholas Aboreden and Maharshi Chakravortee and Richard Sallari and Nelson, {Peter S.} and Kelly, {Kathleen K.} and Graham, {Thomas G.W.} and Xavier Darzacq and Figg, {William D.} and Oyelere, {Adegboyega K.} and Eva Corey and Remi Adelaiye-Ogala and Gryder, {Berkley E.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2024 the Author(s).",

year = "2024",

month = nov,

day = "26",

doi = "10.1073/pnas.2406239121",

language = "English",

volume = "121",

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Kohrt, SE, Novak, EJ, Tapadar, S, Wu, B, Strope, J, Asante, Y, Kim, H, Chang, MS, Gurdak, D, Khalil, A, Rood, M, Raftery, E, Stavreva, D, Nguyen, HM, Brown, LG, Ramser, M, Peer, C, Meyers, WM, Aboreden, N, Chakravortee, M, Sallari, R, Nelson, PS, Kelly, KK, Graham, TGW, Darzacq, X, Figg, WD, Oyelere, AK, Corey, E, Adelaiye-Ogala, R & Gryder, BE 2024, 'Small-molecule disruption of androgen receptor–dependent chromatin clusters', Proceedings of the National Academy of Sciences of the United States of America, vol. 121, no. 48, e2406239121. https://doi.org/10.1073/pnas.2406239121

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T1 - Small-molecule disruption of androgen receptor–dependent chromatin clusters

AU - Kohrt, Sarah E.

AU - Novak, Emily J.

AU - Tapadar, Subhashish

AU - Wu, Bocheng

AU - Strope, Jonathan

AU - Asante, Yaw

AU - Kim, Hyunmin

AU - Chang, Matthew S.

AU - Gurdak, Douglas

AU - Khalil, Athar

AU - Rood, Michael

AU - Raftery, Eric

AU - Stavreva, Diana

AU - Nguyen, Holly M.

AU - Brown, Lisha G.

AU - Ramser, Maddy

AU - Peer, Cody

AU - Meyers, Warren M.

AU - Aboreden, Nicholas

AU - Chakravortee, Maharshi

AU - Sallari, Richard

AU - Nelson, Peter S.

AU - Kelly, Kathleen K.

AU - Graham, Thomas G.W.

AU - Darzacq, Xavier

AU - Figg, William D.

AU - Oyelere, Adegboyega K.

AU - Corey, Eva

AU - Adelaiye-Ogala, Remi

AU - Gryder, Berkley E.

PY - 2024/11/26

Y1 - 2024/11/26

N2 - Sustained androgen receptor (AR) signaling during relapse is a central driver of metastatic castration-resistant prostate cancer (mCRPC). Current AR antagonists, such as enzalutamide, fail to provide long-term benefit for the mCRPC patients who have dramatic increases in AR expression. Here, we report AR antagonists with efficacy in AR-overexpressing models. These molecules bind to the ligand-binding domain of the AR, promote AR localization to the nucleus, yet potently and selectively down-regulate AR-target genes. The molecules BG-15a and the pharmacokinetically optimized BG-15n elicit a decrease in cell and tumor growth in vitro and in vivo in models of mCRPC. BG-15a/n treatment causes the collapse of chromatin loops between enhancers and promoters at key genes in the AR-driven epigenome. AR binding in the promoter, as well as 3D chromatin clustering, is needed for genes to respond. BG-15a/n represent promising agents for treating patients with relapsed AR-driven mCRPC tumors.

AB - Sustained androgen receptor (AR) signaling during relapse is a central driver of metastatic castration-resistant prostate cancer (mCRPC). Current AR antagonists, such as enzalutamide, fail to provide long-term benefit for the mCRPC patients who have dramatic increases in AR expression. Here, we report AR antagonists with efficacy in AR-overexpressing models. These molecules bind to the ligand-binding domain of the AR, promote AR localization to the nucleus, yet potently and selectively down-regulate AR-target genes. The molecules BG-15a and the pharmacokinetically optimized BG-15n elicit a decrease in cell and tumor growth in vitro and in vivo in models of mCRPC. BG-15a/n treatment causes the collapse of chromatin loops between enhancers and promoters at key genes in the AR-driven epigenome. AR binding in the promoter, as well as 3D chromatin clustering, is needed for genes to respond. BG-15a/n represent promising agents for treating patients with relapsed AR-driven mCRPC tumors.

KW - androgen receptor

KW - chromatin architecture

KW - epigenetics

KW - gene regulation

KW - prostate cancer

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