Discovery of a small-molecule inhibitor that traps Polθ on DNA and synergizes with PARP inhibitors
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-...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46593-1 |
| _version_ | 1797219750564069376 |
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| author | 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 Richard T. Pomerantz |
| author_facet | 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 Richard T. Pomerantz |
| author_sort | William Fried |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T12:38:37Z |
| format | Article |
| id | doaj.art-a588334634d94054a3dac469d64b47e7 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T12:38:37Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-a588334634d94054a3dac469d64b47e72024-04-07T11:24:15ZengNature PortfolioNature Communications2041-17232024-04-0115111510.1038/s41467-024-46593-1Discovery of a small-molecule inhibitor that traps Polθ on DNA and synergizes with PARP inhibitorsWilliam Fried0Mrityunjay Tyagi1Leonid Minakhin2Gurushankar Chandramouly3Taylor Tredinnick4Mercy Ramanjulu5William Auerbacher6Marissa Calbert7Timur Rusanov8Trung Hoang9Nikita Borisonnik10Robert Betsch11John J. Krais12Yifan Wang13Umeshkumar M. Vekariya14John Gordon15George Morton16Tatiana Kent17Tomasz Skorski18Neil Johnson19Wayne Childers20Xiaojiang S. Chen21Richard T. Pomerantz22Molecular and Computational Biology, Department of Biological Sciences and Chemistry, University of Southern CaliforniaDepartment of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson UniversityDepartment of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson UniversityDepartment of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson UniversityDepartment of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson UniversityRecombination Therapeutics, Pennsylvania Biotechnology CenterDepartment of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson UniversityDepartment of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson UniversityDepartment of Pharmacology and Regenerative Medicine, University of Illinois at ChicagoJanssen BiotechPolysciences, Inc.Nuclear Dynamics Program, Fox Chase Cancer CenterNuclear Dynamics Program, Fox Chase Cancer CenterNuclear Dynamics Program, Fox Chase Cancer CenterFels Cancer Institute for Personalized MedicineFels Cancer Institute for Personalized MedicineMoulder Center for Drug Discovery Research, Temple University School of PharmacyDepartment of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson UniversityFels Cancer Institute for Personalized MedicineNuclear Dynamics Program, Fox Chase Cancer CenterRecombination Therapeutics, Pennsylvania Biotechnology CenterMolecular and Computational Biology, Department of Biological Sciences and Chemistry, University of Southern CaliforniaDepartment of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson UniversityAbstract 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.https://doi.org/10.1038/s41467-024-46593-1 |
| spellingShingle | 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 Richard T. Pomerantz Discovery of a small-molecule inhibitor that traps Polθ on DNA and synergizes with PARP inhibitors Nature Communications |
| title | Discovery of a small-molecule inhibitor that traps Polθ on DNA and synergizes with PARP inhibitors |
| title_full | Discovery of a small-molecule inhibitor that traps Polθ on DNA and synergizes with PARP inhibitors |
| title_fullStr | Discovery of a small-molecule inhibitor that traps Polθ on DNA and synergizes with PARP inhibitors |
| title_full_unstemmed | Discovery of a small-molecule inhibitor that traps Polθ on DNA and synergizes with PARP inhibitors |
| title_short | Discovery of a small-molecule inhibitor that traps Polθ on DNA and synergizes with PARP inhibitors |
| title_sort | discovery of a small molecule inhibitor that traps polθ on dna and synergizes with parp inhibitors |
| url | https://doi.org/10.1038/s41467-024-46593-1 |
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