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

Fried, William
; 
Tyagi, Mrityunjay
; 
Minakhin, Leonid
; 
Chandramouly, Gurushankar
; 
Tredinnick, Taylor
; 
Ramanjulu, Mercy
; 
Auerbacher, William
; 
Calbert, Marissa
; 
Rusanov, Timur
; 
Hoang, Trung
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Journal article
Date
2024-04-05
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Committee member
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Moulder Center for Drug Discovery Research (Temple University)
Department
Cancer and Cellular Biology
Subject
Structural biology
 Enzyme mechanisms
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https://scholarshare.temple.edu/handle/20.500.12613/11994
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VekariyaEtAl-JournalArticle-2024-04.pdf
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https://doi.org/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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Fried, W., Tyagi, M., Minakhin, L. et al. Discovery of a small-molecule inhibitor that traps Polθ on DNA and synergizes with PARP inhibitors. Nat Commun 15, 2862 (2024). https://doi.org/10.1038/s41467-024-46593-1
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Springer Science and Business Media
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Nature Communications, Vol. 15, Iss. 1
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