Reprogramming CBX8-PRC1 function with a positive allosteric modulator

Junghyun L. Suh; Daniel Bsteh; Bryce Hart; Yibo Si; Tyler M. Weaver; Carina Pribitzer; Roy Lau; Shivani Soni; Heather Ogana; Justin M. Rectenwald; Jacqueline L. Norris; Stephanie H. Cholensky; Cari Sagum; Jessica D. Umana; Dongxu Li; Brian Hardy; Mark T. Bedford; Shannon M. Mumenthaler; Heinz Josef Lenz; Yong Mi Kim; Gang Greg Wang; Ken H. Pearce; Lindsey I. James; Dmitri B. Kireev; Catherine A. Musselman; Stephen V. Frye; Oliver Bell

doi:10.1016/j.chembiol.2021.10.003

Reprogramming CBX8-PRC1 function with a positive allosteric modulator

Junghyun L. Suh, Daniel Bsteh, Bryce Hart, Yibo Si, Tyler M. Weaver, Carina Pribitzer, Roy Lau, Shivani Soni, Heather Ogana, Justin M. Rectenwald, Jacqueline L. Norris, Stephanie H. Cholensky, Cari Sagum, Jessica D. Umana, Dongxu Li, Brian Hardy, Mark T. Bedford, Shannon M. Mumenthaler, Heinz Josef Lenz, Yong Mi KimGang Greg Wang, Ken H. Pearce, Lindsey I. James, Dmitri B. Kireev, Catherine A. Musselman, Stephen V. Frye, Oliver Bell

Epigenetics & Molecular Carcinogenesis

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

10 Scopus citations

Abstract

Canonical targeting of Polycomb repressive complex 1 (PRC1) to repress developmental genes is mediated by cell-type-specific, paralogous chromobox (CBX) proteins (CBX2, 4, 6, 7, and 8). Based on their central role in silencing and their dysregulation associated with human disease including cancer, CBX proteins are attractive targets for small-molecule chemical probe development. Here, we have used a quantitative and target-specific cellular assay to discover a potent positive allosteric modulator (PAM) of CBX8. The PAM activity of UNC7040 antagonizes H3K27me3 binding by CBX8 while increasing interactions with nucleic acids. We show that treatment with UNC7040 leads to efficient and selective eviction of CBX8-containing PRC1 from chromatin, loss of silencing, and reduced proliferation across different cancer cell lines. Our discovery and characterization of UNC7040 not only reveals the most cellularly potent CBX8-specific chemical probe to date, but also corroborates a mechanism of Polycomb regulation by non-specific CBX nucleotide binding activity.

Original language	English (US)
Pages (from-to)	555-571.e11
Journal	Cell Chemical Biology
Volume	29
Issue number	4
DOIs	https://doi.org/10.1016/j.chembiol.2021.10.003
State	Published - Apr 21 2022

Keywords

Polycomb
allosterism
chemical probes
chromatin
chromodomain
epigenetics
methyl-lysine reader
positive allosteric modulator

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

MD Anderson CCSG core facilities

Protein Array and Analysis Core

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10.1016/j.chembiol.2021.10.003

Cite this

Suh, J. L., Bsteh, D., Hart, B., Si, Y., Weaver, T. M., Pribitzer, C., Lau, R., Soni, S., Ogana, H., Rectenwald, J. M., Norris, J. L., Cholensky, S. H., Sagum, C., Umana, J. D., Li, D., Hardy, B., Bedford, M. T., Mumenthaler, S. M., Lenz, H. J., ... Bell, O. (2022). Reprogramming CBX8-PRC1 function with a positive allosteric modulator. Cell Chemical Biology, 29(4), 555-571.e11. https://doi.org/10.1016/j.chembiol.2021.10.003

Suh, JL, Bsteh, D, Hart, B, Si, Y, Weaver, TM, Pribitzer, C, Lau, R, Soni, S, Ogana, H, Rectenwald, JM, Norris, JL, Cholensky, SH, Sagum, C, Umana, JD, Li, D, Hardy, B, Bedford, MT, Mumenthaler, SM, Lenz, HJ, Kim, YM, Wang, GG, Pearce, KH, James, LI, Kireev, DB, Musselman, CA, Frye, SV & Bell, O 2022, 'Reprogramming CBX8-PRC1 function with a positive allosteric modulator', Cell Chemical Biology, vol. 29, no. 4, pp. 555-571.e11. https://doi.org/10.1016/j.chembiol.2021.10.003

@article{5047b6784c7e4269a3d8b6844c0b0720,

title = "Reprogramming CBX8-PRC1 function with a positive allosteric modulator",

abstract = "Canonical targeting of Polycomb repressive complex 1 (PRC1) to repress developmental genes is mediated by cell-type-specific, paralogous chromobox (CBX) proteins (CBX2, 4, 6, 7, and 8). Based on their central role in silencing and their dysregulation associated with human disease including cancer, CBX proteins are attractive targets for small-molecule chemical probe development. Here, we have used a quantitative and target-specific cellular assay to discover a potent positive allosteric modulator (PAM) of CBX8. The PAM activity of UNC7040 antagonizes H3K27me3 binding by CBX8 while increasing interactions with nucleic acids. We show that treatment with UNC7040 leads to efficient and selective eviction of CBX8-containing PRC1 from chromatin, loss of silencing, and reduced proliferation across different cancer cell lines. Our discovery and characterization of UNC7040 not only reveals the most cellularly potent CBX8-specific chemical probe to date, but also corroborates a mechanism of Polycomb regulation by non-specific CBX nucleotide binding activity.",

keywords = "Polycomb, allosterism, chemical probes, chromatin, chromodomain, epigenetics, methyl-lysine reader, positive allosteric modulator",

author = "Suh, {Junghyun L.} and Daniel Bsteh and Bryce Hart and Yibo Si and Weaver, {Tyler M.} and Carina Pribitzer and Roy Lau and Shivani Soni and Heather Ogana and Rectenwald, {Justin M.} and Norris, {Jacqueline L.} and Cholensky, {Stephanie H.} and Cari Sagum and Umana, {Jessica D.} and Dongxu Li and Brian Hardy and Bedford, {Mark T.} and Mumenthaler, {Shannon M.} and Lenz, {Heinz Josef} and Kim, {Yong Mi} and Wang, {Gang Greg} and Pearce, {Ken H.} and James, {Lindsey I.} and Kireev, {Dmitri B.} and Musselman, {Catherine A.} and Frye, {Stephen V.} and Oliver Bell",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2022",

month = apr,

day = "21",

doi = "10.1016/j.chembiol.2021.10.003",

language = "English (US)",

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T1 - Reprogramming CBX8-PRC1 function with a positive allosteric modulator

AU - Suh, Junghyun L.

AU - Bsteh, Daniel

AU - Hart, Bryce

AU - Si, Yibo

AU - Weaver, Tyler M.

AU - Pribitzer, Carina

AU - Lau, Roy

AU - Soni, Shivani

AU - Ogana, Heather

AU - Rectenwald, Justin M.

AU - Norris, Jacqueline L.

AU - Cholensky, Stephanie H.

AU - Sagum, Cari

AU - Umana, Jessica D.

AU - Li, Dongxu

AU - Hardy, Brian

AU - Bedford, Mark T.

AU - Mumenthaler, Shannon M.

AU - Lenz, Heinz Josef

AU - Kim, Yong Mi

AU - Wang, Gang Greg

AU - Pearce, Ken H.

AU - James, Lindsey I.

AU - Kireev, Dmitri B.

AU - Musselman, Catherine A.

AU - Frye, Stephen V.

AU - Bell, Oliver

PY - 2022/4/21

Y1 - 2022/4/21

N2 - Canonical targeting of Polycomb repressive complex 1 (PRC1) to repress developmental genes is mediated by cell-type-specific, paralogous chromobox (CBX) proteins (CBX2, 4, 6, 7, and 8). Based on their central role in silencing and their dysregulation associated with human disease including cancer, CBX proteins are attractive targets for small-molecule chemical probe development. Here, we have used a quantitative and target-specific cellular assay to discover a potent positive allosteric modulator (PAM) of CBX8. The PAM activity of UNC7040 antagonizes H3K27me3 binding by CBX8 while increasing interactions with nucleic acids. We show that treatment with UNC7040 leads to efficient and selective eviction of CBX8-containing PRC1 from chromatin, loss of silencing, and reduced proliferation across different cancer cell lines. Our discovery and characterization of UNC7040 not only reveals the most cellularly potent CBX8-specific chemical probe to date, but also corroborates a mechanism of Polycomb regulation by non-specific CBX nucleotide binding activity.

AB - Canonical targeting of Polycomb repressive complex 1 (PRC1) to repress developmental genes is mediated by cell-type-specific, paralogous chromobox (CBX) proteins (CBX2, 4, 6, 7, and 8). Based on their central role in silencing and their dysregulation associated with human disease including cancer, CBX proteins are attractive targets for small-molecule chemical probe development. Here, we have used a quantitative and target-specific cellular assay to discover a potent positive allosteric modulator (PAM) of CBX8. The PAM activity of UNC7040 antagonizes H3K27me3 binding by CBX8 while increasing interactions with nucleic acids. We show that treatment with UNC7040 leads to efficient and selective eviction of CBX8-containing PRC1 from chromatin, loss of silencing, and reduced proliferation across different cancer cell lines. Our discovery and characterization of UNC7040 not only reveals the most cellularly potent CBX8-specific chemical probe to date, but also corroborates a mechanism of Polycomb regulation by non-specific CBX nucleotide binding activity.

KW - Polycomb

KW - allosterism

KW - chemical probes

KW - chromatin

KW - chromodomain

KW - epigenetics

KW - methyl-lysine reader

KW - positive allosteric modulator

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DO - 10.1016/j.chembiol.2021.10.003

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AN - SCOPUS:85125319491

SN - 2451-9456

VL - 29

SP - 555-571.e11

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 4

ER -

Reprogramming CBX8-PRC1 function with a positive allosteric modulator

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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