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Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance

Abstract:

To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining, without targeting Non-Homologous End Joining. In addition, ART558 elicits DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumour cells and enhances the effects of a...

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Publication status:
Published
Peer review status:
Peer reviewed

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Publisher copy:
10.1038/s41467-021-23463-8

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Institution:
University of Oxford
Division:
MSD
Sub department:
CRUK/MRC Ox Inst for Radiation Oncology
Role:
Author
ORCID:
0000-0001-5196-0552
Publisher:
Springer Nature
Journal:
Nature Communications More from this journal
Volume:
12
Issue:
1
Article number:
3636
Publication date:
2021-06-17
Acceptance date:
2021-04-30
DOI:
ISSN:
2041-1723
Language:
English
Keywords:
Pubs id:
1178302
Local pid:
pubs:1178302
Deposit date:
2021-05-24

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