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Reprogramming CBX8-PRC1 function with a positive allosteric modulator.
Suh, Junghyun L; Bsteh, Daniel; Hart, Bryce; Si, Yibo; Weaver, Tyler M; Pribitzer, Carina; Lau, Roy; Soni, Shivani; Ogana, Heather; Rectenwald, Justin M; Norris, Jacqueline L; Cholensky, Stephanie H; Sagum, Cari; Umana, Jessica D; Li, Dongxu; Hardy, Brian; Bedford, Mark T; Mumenthaler, Shannon M; Lenz, Heinz-Josef; Kim, Yong-Mi; Wang, Gang Greg; Pearce, Ken H; James, Lindsey I; Kireev, Dmitri B; Musselman, Catherine A; Frye, Stephen V; Bell, Oliver.
Afiliação
  • Suh JL; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Bsteh D; Department of Biochemistry and Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
  • Hart B; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Si Y; Department of Biochemistry and Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
  • Weaver TM; University of Iowa, Department of Biochemistry, Iowa City, IA 52242, USA.
  • Pribitzer C; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, 1030 Vienna, Austria.
  • Lau R; Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USA.
  • Soni S; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
  • Ogana H; Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90027, USA.
  • Rectenwald JM; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Norris JL; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Cholensky SH; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Sagum C; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
  • Umana JD; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Li D; Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Hardy B; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Bedford MT; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
  • Mumenthaler SM; Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA 90033, USA; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
  • Lenz HJ; Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
  • Kim YM; Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90027, USA.
  • Wang GG; Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Pearce KH; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • James LI; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of No
  • Kireev DB; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Musselman CA; University of Iowa, Department of Biochemistry, Iowa City, IA 52242, USA; University of Colorado Anschutz Medical Campus, Department of Biochemistry and Molecular Genetics, Aurora, CO 80045, USA.
  • Frye SV; Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, UNC School of Medicine, University of No
  • Bell O; Department of Biochemistry and Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, 1030 Vienna, Austria. Electronic
Cell Chem Biol ; 29(4): 555-571.e11, 2022 04 21.
Article em En | MEDLINE | ID: mdl-34715055
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Complexo Repressor Polycomb 1 / Neoplasias Limite: Humans Idioma: En Revista: Cell Chem Biol Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Complexo Repressor Polycomb 1 / Neoplasias Limite: Humans Idioma: En Revista: Cell Chem Biol Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos