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Discovery of a small-molecule inhibitor that traps Polθ on DNA and synergizes with PARP inhibitors

Author

Listed:
  • William Fried

    (University of Southern California)

  • Mrityunjay Tyagi

    (Sidney Kimmel Cancer Center, Thomas Jefferson University)

  • Leonid Minakhin

    (Sidney Kimmel Cancer Center, Thomas Jefferson University)

  • Gurushankar Chandramouly

    (Sidney Kimmel Cancer Center, Thomas Jefferson University)

  • Taylor Tredinnick

    (Sidney Kimmel Cancer Center, Thomas Jefferson University)

  • Mercy Ramanjulu

    (Pennsylvania Biotechnology Center)

  • William Auerbacher

    (Sidney Kimmel Cancer Center, Thomas Jefferson University)

  • Marissa Calbert

    (Sidney Kimmel Cancer Center, Thomas Jefferson University
    Fels Cancer Institute for Personalized Medicine)

  • Timur Rusanov

    (University of Illinois at Chicago)

  • Trung Hoang

    (Janssen Biotech)

  • Nikita Borisonnik

    (Inc.)

  • Robert Betsch

    (Fox Chase Cancer Center)

  • John J. Krais

    (Fox Chase Cancer Center)

  • Yifan Wang

    (Fox Chase Cancer Center)

  • Umeshkumar M. Vekariya

    (Fels Cancer Institute for Personalized Medicine
    Temple University Lewis Katz School of Medicine)

  • John Gordon

    (Fels Cancer Institute for Personalized Medicine)

  • George Morton

    (Temple University School of Pharmacy)

  • Tatiana Kent

    (Sidney Kimmel Cancer Center, Thomas Jefferson University)

  • Tomasz Skorski

    (Fels Cancer Institute for Personalized Medicine
    Temple University Lewis Katz School of Medicine)

  • Neil Johnson

    (Fox Chase Cancer Center)

  • Wayne Childers

    (Pennsylvania Biotechnology Center
    Temple University School of Pharmacy)

  • Xiaojiang S. Chen

    (University of Southern California
    Pennsylvania Biotechnology Center)

  • Richard T. Pomerantz

    (Sidney Kimmel Cancer Center, Thomas Jefferson University
    Pennsylvania Biotechnology Center)

Abstract

The DNA damage response (DDR) protein DNA Polymerase θ (Polθ) is synthetic lethal with homologous recombination (HR) factors and is therefore a promising drug target in BRCA1/2 mutant cancers. We discover an allosteric Polθ inhibitor (Polθi) class with 4–6 nM IC50 that selectively kills HR-deficient cells and acts synergistically with PARP inhibitors (PARPi) in multiple genetic backgrounds. X-ray crystallography and biochemistry reveal that Polθi selectively inhibits Polθ polymerase (Polθ-pol) in the closed conformation on B-form DNA/DNA via an induced fit mechanism. In contrast, Polθi fails to inhibit Polθ-pol catalytic activity on A-form DNA/RNA in which the enzyme binds in the open configuration. Remarkably, Polθi binding to the Polθ-pol:DNA/DNA closed complex traps the polymerase on DNA for more than forty minutes which elucidates the inhibitory mechanism of action. These data reveal a unique small-molecule DNA polymerase:DNA trapping mechanism that induces synthetic lethality in HR-deficient cells and potentiates the activity of PARPi.

Suggested Citation

  • William Fried & Mrityunjay Tyagi & Leonid Minakhin & Gurushankar Chandramouly & Taylor Tredinnick & Mercy Ramanjulu & William Auerbacher & Marissa Calbert & Timur Rusanov & Trung Hoang & Nikita Boriso, 2024. "Discovery of a small-molecule inhibitor that traps Polθ on DNA and synergizes with PARP inhibitors," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46593-1
    DOI: 10.1038/s41467-024-46593-1
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    References listed on IDEAS

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    1. Wanjuan Feng & Dennis A. Simpson & Juan Carvajal-Garcia & Brandon A. Price & Rashmi J. Kumar & Lisle E. Mose & Richard D. Wood & Naim Rashid & Jeremy E. Purvis & Joel S. Parker & Dale A. Ramsden & Gao, 2019. "Genetic determinants of cellular addiction to DNA polymerase theta," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    2. Wouter Koole & Robin van Schendel & Andrea E. Karambelas & Jane T. van Heteren & Kristy L. Okihara & Marcel Tijsterman, 2014. "A Polymerase Theta-dependent repair pathway suppresses extensive genomic instability at endogenous G4 DNA sites," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
    3. Raphael Ceccaldi & Jessica C. Liu & Ravindra Amunugama & Ildiko Hajdu & Benjamin Primack & Mark I. R. Petalcorin & Kevin W. O’Connor & Panagiotis A. Konstantinopoulos & Stephen J. Elledge & Simon J. B, 2015. "Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair," Nature, Nature, vol. 518(7538), pages 258-262, February.
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