2. Academic Validation
  3. Discovery of a small-molecule inhibitor that traps Polθ on DNA and synergizes with PARP inhibitors

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

  • Nat Commun. 2024 Apr 5;15(1):2862. doi: 10.1038/s41467-024-46593-1.
William Fried # 1,  Mrityunjay Tyagi # 2,  Leonid Minakhin 2,  Gurushankar Chandramouly 2,  Taylor Tredinnick 2,  Mercy Ramanjulu 3,  William Auerbacher 2,  Marissa Calbert 2 4,  Timur Rusanov 5,  Trung Hoang 6,  Nikita Borisonnik 7,  Robert Betsch 8,  John J Krais 8,  Yifan Wang 8,  Umeshkumar M Vekariya 4 9,  John Gordon 4,  George Morton 10,  Tatiana Kent 2,  Tomasz Skorski 4 9,  Neil Johnson 8,  Wayne Childers 3 10,  Xiaojiang S Chen 1 3,  Richard T Pomerantz 11 12
Affiliations

Affiliations

  • 1 Molecular and Computational Biology, Department of Biological Sciences and Chemistry, University of Southern California, Los Angeles, CA, USA.
  • 2 Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
  • 3 Recombination Therapeutics, Pennsylvania Biotechnology Center, Doylestown, PA, 18902, USA.
  • 4 Fels Cancer Institute for Personalized Medicine, Philadelphia, PA, USA.
  • 5 Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
  • 6 Janssen Biotech, Malvern, PA, 19355, USA.
  • 7 Polysciences, Inc., Huntingdon Valley, PA, USA.
  • 8 Nuclear Dynamics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
  • 9 Department of Cancer and Cellular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA.
  • 10 Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA, USA.
  • 11 Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA. richard.pomerantz@jefferson.edu.
  • 12 Recombination Therapeutics, Pennsylvania Biotechnology Center, Doylestown, PA, 18902, USA. richard.pomerantz@jefferson.edu.
  • # Contributed equally.
PMID: 38580648 DOI: 10.1038/s41467-024-46593-1
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.

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