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

William Fried, Mrityunjay Tyagi, Leonid Minakhin, Gurushankar Chandramouly, Taylor Tredinnick, Mercy Ramanjulu, William Auerbacher, Marissa Calbert, Timur Rusanov, Trung Hoang, Nikita Borisonnik, Robert Betsch, John J. Krais, Yifan Wang, Umeshkumar M. Vekariya, John Gordon, George Morton, Tatiana Kent, Tomasz Skorski, Neil Johnson, Wayne Childers, Xiaojiang S. Chen and Richard T. Pomerantz ()
Additional contact information
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
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
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
Neil Johnson: Fox Chase Cancer Center
Wayne Childers: Pennsylvania Biotechnology Center
Xiaojiang S. Chen: University of Southern California
Richard T. Pomerantz: Sidney Kimmel Cancer Center, Thomas Jefferson University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46593-1

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