ArticleJournal of medicinal chemistry2022
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Open access · greenAbstract read
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Article in Journal of medicinal chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
0numbers the graph read from it
0cells of the map it votes in
42citing papers in PubMed
4.8field-weighted citation impact, top 4% of its field
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Who cites it
42 citing papers in PubMed, 62 citations in OpenAlex.
- DNA polymerase theta (Polθ): a novel candidate for targeted cancer therapy.Cancer biology & therapy · 2026Review
- Article
- The Pharmacologic Profile of ART6043, a First-in-Class Clinical DNA Polymerase Theta Polymerase Domain Inhibitor Potentiating PARP Inhibitor Efficacy.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Targeting Polθ Helicase with RP-3467: Preclinical Validation and Clinical Response in a gmedRxiv : the preprint server for health sciences · 2026Article
- Defective microhomology-mediated end joining inScience advances · 2026Article
- Aldehyde Detoxification in Cancer: Metabolic Guardians of the Genome.Biomolecules · 2026Review
- Polθ activity modulates sensitivity to standard therapies in DNMT3A-deficient leukemia.Cell reports. Medicine · 2026Article
- Overcoming Resistance to PARP Inhibitors in BRCA-Mutated Cancers: Mechanisms and Therapeutic Strategies.Journal of Cancer · 2026Review
- Review
- Coordinated transfer of DNA between Pol θ and Pol δ resets microhomology choice during double-strand break repair.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Megabase-scale loss of heterozygosity provoked by CRISPR-Cas9 DNA double-strand breaks.Molecular cell · 2025Article
- RTx-303, an Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates PARP Inhibitors in BRCA Mutant Tumors.Journal of medicinal chemistry · 2025Article
- Polymerase Ѳ inhibitors combinations with approved and investigational agents in patient-derived tumor multi-cell type (mct) spheroids.Experimental and molecular pathology · 2025Article
- Article
- RNA transcripts serve as a template for double-strand break repair in human cells.Nature communications · 2025Article
- Structural basis of error-prone DNA synthesis by DNA polymerase θ.Nature communications · 2025Article
- Cryo-EM Structures of the Plasmodium falciparum Apicoplast DNA Polymerase.Journal of molecular biology · 2024Article
- Targeting the DNA damage response in cancer.MedComm · 2024Review
- Polθ: emerging synthetic lethal partner in homologous recombination-deficient tumors.Cancer gene therapy · 2024Review
- Microhomology-Mediated End-Joining Chronicles: Tracing the Evolutionary Footprints of Genome Protection.Annual review of cell and developmental biology · 2024Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
42 authors at 6 institutions in 3 countries.
Monica BubenikRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.ORCID 0000-0002-1449-2312
Pavel MaderLunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada.ORCID 0000-0002-0820-2761
Philippe MochirianRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Fréderic ValléeRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Jillian ClarkRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Jean-François TruchonRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Alexander L PerrymanRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Victor PauLunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada.ORCID 0000-0002-3093-2330
Igor KurinovDepartment of Chemistry and Chemical Biology, NE-CAT, Argonne, Cornell University, Illinois, New York 60439, United States.
Karl E ZahnRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Marie-Eve LeclaireRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Robert PappRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Marie-Claude MathieuRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Martine HamelRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Nicole M DuffyRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Claude GodboutRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Matias Casas-SelvesRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Jean-Pierre FalgueyretRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Prasamit S BaruahRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Olivier NicolasRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Rino StoccoRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Hugo PoirierRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Giovanni MartinoRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Alexanne Bonneau FortinRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Anne RoulstonRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Amandine ChefsonVentus Therapeutics, 7150 Frederick-Banting Suite 200, Montréal, Québec H4S 2A1, Canada.
Stéphane DorichVentus Therapeutics, 7150 Frederick-Banting Suite 200, Montréal, Québec H4S 2A1, Canada.
Miguel St-OngeVentus Therapeutics, 7150 Frederick-Banting Suite 200, Montréal, Québec H4S 2A1, Canada.
Purvish PatelVentus Therapeutics, 7150 Frederick-Banting Suite 200, Montréal, Québec H4S 2A1, Canada.
Charles PellerinVentus Therapeutics, 7150 Frederick-Banting Suite 200, Montréal, Québec H4S 2A1, Canada.
Stéphane CiblatVentus Therapeutics, 7150 Frederick-Banting Suite 200, Montréal, Québec H4S 2A1, Canada.
Thomas PinterVentus Therapeutics, 7150 Frederick-Banting Suite 200, Montréal, Québec H4S 2A1, Canada.
Francis BarabéParaza Pharma Inc., 2525 Ave. Marie Curie, Montréal, Québec H4S 1Z9, Canada.
Majida El BakkouriParaza Pharma Inc., 2525 Ave. Marie Curie, Montréal, Québec H4S 1Z9, Canada.
Paranjay ParikhPiramal Pharma Ltd., Plot No. 18, Village Matoda, Taluka: Sanand, Ahmedabad, Gujarat 382213, India.
Christian GervaisNational Research Council of Canada, 6100 Royalmount Avenue, Montréal, Québec H4P 2R2, Canada.
Agnel SfeirMolecular Biology Program, Sloan Kettering Institute, MSKCC, 430 E 67th Street, New York, New York 10065, United States.
Yael MamaneRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Stephen J MorrisRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
W Cameron BlackRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Frank SicheriLunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada.ORCID 0000-0002-9824-2117
Michel GallantRepare Therapeutics, 7171 Frederick-Banting, Building 2, Montréal, Québec H4S 1Z9, Canada.
Lunenfeld-Tanenbaum Research Institute · CAParaza Pharma (Canada) · CAArgonne National Laboratory · USMemorial Sloan Kettering Cancer Center · USNational Research Council Canada · CAPiramal (India) · IN
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Hongbiao Carl Lekaye · 1985 to 2026
$347.4MUser Training and OutreachP30GM124165 · NIGMS · CORNELL UNIVERSITY · PI Nozomi Ando, J Christopher Fromme · 2018 to 2026
$34.2MPixel Array Detector for Macromolecular CrystallographyS10OD021527 · OD · CORNELL UNIVERSITY · PI EALICK, STEVEN E · 2016 to 2016
$2.0MNCI NIH HHS P30 CA008748NIGMS NIH HHS P30 GM124165NIH HHS S10 OD021527
Abstract
DNA polymerase theta (Polθ) is an attractive synthetic lethal target for drug discovery, predicted to be efficacious against breast and ovarian cancers harboring BRCA-mutant alleles. Here, we describe our hit-to-lead efforts in search of a selective inhibitor of human Polθ (encoded by POLQ). A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods. Structure-based drug design efforts along with optimization of cellular potency and ADME ultimately led to the identification of
Indexed as
DNA-Directed DNA PolymeraseOvarian NeoplasmsAnimalsDNA ReplicationDrug DesignDrug DiscoveryFemaleHumansMiceDNA-Directed DNA Polymerase
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.