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Publication Abstract from PubMed

DNA polymerase theta (Poltheta) 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 Poltheta 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.

The Discovery of RP-2119: A Potent, Selective, and Orally Bioavailable Poltheta ATPase Inhibitor.,Mochirian P, Papp R, Mathieu MC, Ferraro GB, Dietrich E, Liu B, Bendahan D, Perryman AL, Surprenant S, Fournier S, Barzili BL, Bonneau-Fortin A, Yin SY, Leclaire ME, Patel C, Poirier H, Save S, Mathieu Y, Morin N, Godbout C, Burston HE, Zahn KE, Attia MA, Pinter T, Barabe F, Parikh P, Jagani C, Kang G, Scapin G, Mamane Y, Sfeir A, Mader P, Sicheri F, Zimmermann M, Roulston A, Morris SJ, Black WC, Gallant M J Med Chem. 2025 Sep 8. doi: 10.1021/acs.jmedchem.5c02103. PMID:40920169^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.