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Potent and selective SETDB1 covalent negative allosteric modulator reduces methyltransferase activity in cells

Author

Listed:
  • Mélanie Uguen

    (University of North Carolina at Chapel Hill)

  • Devan J. Shell

    (University of North Carolina at Chapel Hill)

  • Madhushika Silva

    (University of Toronto)

  • Yu Deng

    (University of North Carolina at Chapel Hill School of Medicine
    The University of North Carolina at Chapel Hill)

  • Fengling Li

    (University of Toronto)

  • Magdalena M. Szewczyk

    (University of Toronto)

  • Ka Yang

    (Harvard Medical School)

  • Yani Zhao

    (University of North Carolina at Chapel Hill)

  • Michael A. Stashko

    (University of North Carolina at Chapel Hill)

  • Jacqueline L. Norris-Drouin

    (University of North Carolina at Chapel Hill)

  • Jarod M. Waybright

    (University of North Carolina at Chapel Hill
    Design Therapeutics)

  • Serap Beldar

    (University of Toronto)

  • Justin M. Rectenwald

    (University of North Carolina at Chapel Hill)

  • Angie L. Mordant

    (University of North Carolina at Chapel Hill)

  • Thomas S. Webb

    (University of North Carolina at Chapel Hill)

  • Laura E. Herring

    (University of North Carolina at Chapel Hill)

  • Cheryl H. Arrowsmith

    (University of Toronto)

  • Suzanne Ackloo

    (University of Toronto)

  • Steven P. Gygi

    (Harvard Medical School)

  • Robert K. McGinty

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill School of Medicine
    The University of North Carolina at Chapel Hill)

  • Dalia Barsyte-Lovejoy

    (University of Toronto)

  • Pengda Liu

    (University of North Carolina at Chapel Hill School of Medicine
    The University of North Carolina at Chapel Hill)

  • Levon Halabelian

    (University of Toronto)

  • Lindsey I. James

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill School of Medicine)

  • Kenneth H. Pearce

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill School of Medicine)

  • Stephen V. Frye

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill School of Medicine)

Abstract

A promising drug target, SETDB1, is a dual methyl-lysine (Kme) reader and methyltransferase implicated in cancer and neurodegenerative disease progression. To help understand the role of the triple Tudor domain (3TD) of SETDB1, its Kme reader, we first identify a low micromolar potency small molecule ligand, UNC6535, which occupies simultaneously both the TD2 and TD3 reader binding sites. Further optimization leads to the discovery of UNC10013, a covalent 3TD ligand targeting Cys385 of SETDB1. UNC10013 is potent with a kinact/KI of 1.0 × 106 M−1s−1 and demonstrates proteome-wide selectivity. In cells, negative allosteric modulation of SETDB1-mediated Akt methylation occurs after treatment with UNC10013. Therefore, UNC10013 is a potent, selective, and cell-active covalent ligand for the 3TD of SETDB1, demonstrating negative allosteric modulator properties and making it a promising tool to study the biological role of SETDB1 in disease progression.

Suggested Citation

  • Mélanie Uguen & Devan J. Shell & Madhushika Silva & Yu Deng & Fengling Li & Magdalena M. Szewczyk & Ka Yang & Yani Zhao & Michael A. Stashko & Jacqueline L. Norris-Drouin & Jarod M. Waybright & Serap , 2025. "Potent and selective SETDB1 covalent negative allosteric modulator reduces methyltransferase activity in cells," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57005-3
    DOI: 10.1038/s41467-025-57005-3
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    References listed on IDEAS

    as
    1. Qi Fei & Ke Shang & Jianhua Zhang & Shannon Chuai & Desheng Kong & Tianlun Zhou & Shijun Fu & Ying Liang & Chong Li & Zhi Chen & Yuan Zhao & Zhengtian Yu & Zheng Huang & Min Hu & Haiyan Ying & Zhui Ch, 2015. "Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
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