Small-Molecule Modulators of Methyl-Lysine Binding for the CBX7 Chromodomain

Ren, Chunyan; Morohashi, Keita; Plotnikov, Alexander N.; Jakoncic, Jean; Smith, Steven G.; Li, Jiaojie; Zeng, Lei; Rodriguez, Yoel; Stojanoff, Vivian; Walsh, Martin; Zhou, Ming-Ming

doi:10.1016/j.chembiol.2014.11.021

Title: Small-Molecule Modulators of Methyl-Lysine Binding for the CBX7 Chromodomain

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Abstract

Chromobox homolog 7 (CBX7) plays an important role in gene transcription in a wide array of cellular processes, ranging from stem cell self-renewal and differentiation to tumor progression. CBX7 functions through its N-terminal chromodomain (ChD), which recognizes tri-methylated lysine 27 of histone 3 (H3K27me3), a conserved epigenetic mark that signifies gene transcriptional repression. Here in this study, we report discovery of small molecules that inhibit CBX7ChD binding to H3K27me3. Our crystal structures reveal the binding modes of these molecules that compete against H3K27me3 binding through interactions with key residues in the methyl-lysine binding pocket of CBX7ChD. We further show that a lead compound MS37452, derepresses transcription of Polycomb repressive complex target gene p16/CDKN2A by displacing CBX7 binding to the INK4A/ARF locus in prostate cancer cells. Ultimately, these small molecules have the potential to be developed into high-potency chemical modulators that target CBX7 functions in gene transcription in different disease pathways.

Authors:: Ren, Chunyan; Morohashi, Keita; Plotnikov, Alexander N.; Jakoncic, Jean; Smith, Steven G.; Li, Jiaojie; Zeng, Lei; Rodriguez, Yoel; Stojanoff, Vivian; Walsh, Martin; Zhou, Ming-Ming

Publication Date:: Sun Feb 01 00:00:00 EST 2015

Research Org.:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Org.:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

OSTI Identifier:: 1238690

Alternate Identifier(s):: OSTI ID: 1229350; OSTI ID: 1233885

Report Number(s):: BNL-111425-2015-JA
Journal ID: ISSN 1074-5521; S1074552115000022; PII: S1074552115000022

Grant/Contract Number:: AC02-98CH10886; SC00112704; GM0080

Resource Type:: Published Article

Journal Name:: Chemistry & Biology

Additional Journal Information:: Journal Name: Chemistry & Biology Journal Volume: 22 Journal Issue: 2; Journal ID: ISSN 1074-5521

Publisher:: Elsevier

Country of Publication:: United Kingdom

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats


                    Ren, Chunyan, Morohashi, Keita, Plotnikov, Alexander N., Jakoncic, Jean, Smith, Steven G., Li, Jiaojie, Zeng, Lei, Rodriguez, Yoel, Stojanoff, Vivian, Walsh, Martin, and Zhou, Ming-Ming. Small-Molecule Modulators of Methyl-Lysine Binding for the CBX7 Chromodomain.  United Kingdom: N. p., 2015. 
Web.  doi:10.1016/j.chembiol.2014.11.021.

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                    Ren, Chunyan, Morohashi, Keita, Plotnikov, Alexander N., Jakoncic, Jean, Smith, Steven G., Li, Jiaojie, Zeng, Lei, Rodriguez, Yoel, Stojanoff, Vivian, Walsh, Martin, & Zhou, Ming-Ming. Small-Molecule Modulators of Methyl-Lysine Binding for the CBX7 Chromodomain.  United Kingdom.  https://doi.org/10.1016/j.chembiol.2014.11.021

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                    Ren, Chunyan, Morohashi, Keita, Plotnikov, Alexander N., Jakoncic, Jean, Smith, Steven G., Li, Jiaojie, Zeng, Lei, Rodriguez, Yoel, Stojanoff, Vivian, Walsh, Martin, and Zhou, Ming-Ming. Sun .  
"Small-Molecule Modulators of Methyl-Lysine Binding for the CBX7 Chromodomain".  United Kingdom.  https://doi.org/10.1016/j.chembiol.2014.11.021.

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@article{osti_1238690,

  title        = {Small-Molecule Modulators of Methyl-Lysine Binding for the CBX7 Chromodomain},

  author       = {Ren, Chunyan and Morohashi, Keita and Plotnikov, Alexander N. and Jakoncic, Jean and Smith, Steven G. and Li, Jiaojie and Zeng, Lei and Rodriguez, Yoel and Stojanoff, Vivian and Walsh, Martin and Zhou, Ming-Ming},

  abstractNote = {Chromobox homolog 7 (CBX7) plays an important role in gene transcription in a wide array of cellular processes, ranging from stem cell self-renewal and differentiation to tumor progression. CBX7 functions through its N-terminal chromodomain (ChD), which recognizes tri-methylated lysine 27 of histone 3 (H3K27me3), a conserved epigenetic mark that signifies gene transcriptional repression. Here in this study, we report discovery of small molecules that inhibit CBX7ChD binding to H3K27me3. Our crystal structures reveal the binding modes of these molecules that compete against H3K27me3 binding through interactions with key residues in the methyl-lysine binding pocket of CBX7ChD. We further show that a lead compound MS37452, derepresses transcription of Polycomb repressive complex target gene p16/CDKN2A by displacing CBX7 binding to the INK4A/ARF locus in prostate cancer cells. Ultimately, these small molecules have the potential to be developed into high-potency chemical modulators that target CBX7 functions in gene transcription in different disease pathways.},

  doi          = {10.1016/j.chembiol.2014.11.021},

  journal      = {Chemistry & Biology},

  number       = 2,

  volume       = 22,

  place        = {United Kingdom},

  year         = {Sun Feb 01 00:00:00 EST 2015},

  month        = {Sun Feb 01 00:00:00 EST 2015}

}

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