The discovery of RP-2119: A potent, selective, and orally bioavailable Polθ ATPase inhibitor Journal Article
| Authors: | Mochirian, P.; Papp, R.; Mathieu, M. C.; Ferraro, G. B.; Dietrich, E.; Liu, B.; Bendahan, D.; Perryman, A. L.; Surprenant, S.; Fournier, S.; Barzili, B. L.; Bonneau-Fortin, A.; Yin, S. Y.; Leclaire, M. E.; Patel, C.; Poirier, H.; Save, S.; Mathieu, Y.; Morin, N.; Godbout, C.; Burston, H. E.; Zahn, K. E.; Attia, M. A.; Pinter, T.; Barabé, F.; Parikh, P.; Jagani, C.; Kang, G.; Scapin, G.; Mamane, Y.; Sfeir, A.; Mader, P.; Sicheri, F.; Zimmermann, M.; Roulston, A.; Morris, S. J.; Black, W. C.; Gallant, M. |
| Article Title: | The discovery of RP-2119: A potent, selective, and orally bioavailable Polθ ATPase inhibitor |
| Abstract: | <p>DNA polymerase theta (Pol theta) 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 Pol theta 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.</p> |
| Keywords: | tumors; repair; bypass; dna-polymerase; helicase domain |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 68 |
| Issue: | 18 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Publication status: | Published |
| Date Published: | 2025-09-25 |
| Online Publication Date: | 2025-09-08 |
| Start Page: | 19726 |
| End Page: | 19745 |
| Language: | English |
| ACCESSION: | WOS:001566328100001 |
| DOI: | 10.1021/acs.jmedchem.5c02103 |
| PROVIDER: | wos |
| PUBMED: | 40920169 |
| Notes: | Article -- Source: Wos |
