2. Academic Validation
  3. The Discovery of RP-2119: A Potent, Selective, and Orally Bioavailable Polθ ATPase Inhibitor

The Discovery of RP-2119: A Potent, Selective, and Orally Bioavailable Polθ ATPase Inhibitor

  • J Med Chem. 2025 Sep 25;68(18):19726-19745. doi: 10.1021/acs.jmedchem.5c02103.
Philippe Mochirian 1,  Robert Papp 1,  Marie-Claude Mathieu 1,  Gino B Ferraro 1,  Evelyne Dietrich 1,  Bingcan Liu 1,  David Bendahan 1,  Alexander L Perryman 1,  Simon Surprenant 1,  Sara Fournier 1,  Bita Lotfollahzadeh Barzili 1,  Alexanne Bonneau-Fortin 1,  Shou Yun Yin 1,  Marie-Eve Leclaire 1,  Charmi Patel 1,  Hugo Poirier 1,  Sai Save 1,  Yann Mathieu 1,  Nicolas Morin 1,  Claude Godbout 1,  Helen E Burston 1,  Karl E Zahn 1,  Mohamed A Attia 1,  Thomas Pinter 2,  Francis Barabé 2,  Paranjay Parikh 3,  Chandresh Jagani 3,  Gyunghoon Kang 4,  Giovanna Scapin 4,  Yael Mamane 1,  Agnel Sfeir 5,  Pavel Mader 6,  Frank Sicheri 6,  Michal Zimmermann 1,  Anne Roulston 1,  Stephen J Morris 1,  W Cameron Black 1,  Michel Gallant 1
Affiliations

Affiliations

  • 1 Repare Therapeutics, 7171 Frederick-Banting, Building 2, H4S 1Z9 Montréal, Québec, Canada.
  • 2 Paraza Pharma Inc., 2525 Ave. Marie Curie, Montréal, Québec H4S 1Z9, Canada.
  • 3 Piramal Pharma Ltd., Village Matoda, Taluka: Sanand, Ahmedabad 382213, Gujarat,India.
  • 4 NanoImaging Services, 4940 Carroll Canyon Rd UNIT 115, San Diego, California 92121, United States.
  • 5 Molecular Biology Program, Sloan Kettering Institute, MSKCC, 430 E 67th Street, New York, New York 10065, United States.
  • 6 Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada.
PMID: 40920169 DOI: 10.1021/acs.jmedchem.5c02103
Abstract

DNA Polymerase theta (Polθ) plays a critical role in repairing DNA double-strand breaks through microhomology-mediated end joining (MMEJ) and has emerged as a key synthetic lethal drug target in cancers with homologous recombination (HR) deficiencies. Its inhibition has shown a strong potential to synergize with PARP inhibitors, particularly in tumors with deleterious BRCA1 or BRCA2 mutations. Here, we describe the discovery and preclinical development of RP-2119, a selective, potent, and bioavailable Polθ ATPase inhibitor. Starting from a high-throughput ATPase screen combined with literature insights, key vectors for enhancing potency were identified by structural studies using single-particle cryo-electron microscopy (cryo-EM) that revealed the inhibitor binding site. Further optimization of potency and ADME properties led to the identification of RP-2119 with robust in vitro cellular activity in a wide range of HR-deficient Cancer cell lines. In HR-deficient cell line- and patient-derived mouse xenografts, RP-2119 demonstrated strong synergy with the PARP Inhibitor, olaparib, without exacerbating its hematological toxicity.

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