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
  • 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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