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Discovery of a chemical probe for PRDM9

Author

Listed:
  • Abdellah Allali-Hassani

    (Structural Genomics Consortium, University of Toronto)

  • Magdalena M. Szewczyk

    (Structural Genomics Consortium, University of Toronto)

  • Danton Ivanochko

    (Structural Genomics Consortium, University of Toronto
    Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto)

  • Shawna L. Organ

    (Structural Genomics Consortium, University of Toronto)

  • Jabez Bok

    (Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR))

  • Jessica Sook Yuin Ho

    (Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR))

  • Florence P. H. Gay

    (Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR))

  • Fengling Li

    (Structural Genomics Consortium, University of Toronto)

  • Levi Blazer

    (Structural Genomics Consortium, University of Toronto)

  • Mohammad S. Eram

    (Structural Genomics Consortium, University of Toronto)

  • Levon Halabelian

    (Structural Genomics Consortium, University of Toronto)

  • David Dilworth

    (Structural Genomics Consortium, University of Toronto)

  • Genna M. Luciani

    (Structural Genomics Consortium, University of Toronto)

  • Evelyne Lima-Fernandes

    (Structural Genomics Consortium, University of Toronto)

  • Qin Wu

    (Structural Genomics Consortium, University of Toronto)

  • Peter Loppnau

    (Structural Genomics Consortium, University of Toronto)

  • Nathan Palmer

    (Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR))

  • S. Zakiah A. Talib

    (Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR))

  • Peter J. Brown

    (Structural Genomics Consortium, University of Toronto)

  • Matthieu Schapira

    (Structural Genomics Consortium, University of Toronto
    Department of Pharmacology and Toxicology, University of Toronto)

  • Philipp Kaldis

    (Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)
    National University of Singapore (NUS), Department of Biochemistry)

  • Ronan C. O’Hagan

    (Merck & Co., Inc.)

  • Ernesto Guccione

    (Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)
    Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
    Department of Pharmacological Sciences and Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai)

  • Dalia Barsyte-Lovejoy

    (Structural Genomics Consortium, University of Toronto
    Nature Research Center)

  • Cheryl H. Arrowsmith

    (Structural Genomics Consortium, University of Toronto
    Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto)

  • John M. Sanders

    (Merck & Co., Inc.)

  • Solomon D. Kattar

    (Merck & Co., Inc.)

  • D. Jonathan Bennett

    (Merck & Co., Inc.)

  • Benjamin Nicholson

    (Merck & Co., Inc.)

  • Masoud Vedadi

    (Structural Genomics Consortium, University of Toronto
    Department of Pharmacology and Toxicology, University of Toronto)

Abstract

PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant expression of PRDM9 in oncogenesis and genome instability. Here we report the discovery of MRK-740, a potent (IC50: 80 ± 16 nM), selective and cell-active PRDM9 inhibitor (Chemical Probe). MRK-740 binds in the substrate-binding pocket, with unusually extensive interactions with the cofactor S-adenosylmethionine (SAM), conferring SAM-dependent substrate-competitive inhibition. In cells, MRK-740 specifically and directly inhibits H3K4 methylation at endogenous PRDM9 target loci, whereas the closely related inactive control compound, MRK-740-NC, does not. The discovery of MRK-740 as a chemical probe for the PRDM subfamily of methyltransferases highlights the potential for exploiting SAM in targeting SAM-dependent methyltransferases.

Suggested Citation

  • Abdellah Allali-Hassani & Magdalena M. Szewczyk & Danton Ivanochko & Shawna L. Organ & Jabez Bok & Jessica Sook Yuin Ho & Florence P. H. Gay & Fengling Li & Levi Blazer & Mohammad S. Eram & Levon Hala, 2019. "Discovery of a chemical probe for PRDM9," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13652-x
    DOI: 10.1038/s41467-019-13652-x
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    Cited by:

    1. Yao, Yu & Shi, Lingfeng & Tian, Hua & Wang, Xuan & Sun, Xiaocun & Zhang, Yonghao & Wu, Zirui & Sun, Rui & Shu, Gequn, 2022. "Combined cooling and power cycle for engine waste heat recovery using CO2-based mixtures," Energy, Elsevier, vol. 240(C).
    2. Shohei Takase & Takashi Hiroyama & Fumiyuki Shirai & Yuki Maemoto & Akiko Nakata & Mayumi Arata & Seiji Matsuoka & Takeshi Sonoda & Hideaki Niwa & Shin Sato & Takashi Umehara & Mikako Shirouzu & Yosuk, 2023. "A specific G9a inhibitor unveils BGLT3 lncRNA as a universal mediator of chemically induced fetal globin gene expression," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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