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TitleThe Discovery of RP-2119: A Potent, Selective, and Orally Bioavailable Polθ ATPase Inhibitor.
Journal, issue, pagesJ Med Chem, Vol. 68, Issue 18, Page 19726-19745, Year 2025
Publish dateSep 25, 2025
AuthorsPhilippe Mochirian / Robert Papp / Marie-Claude Mathieu / Gino B Ferraro / Evelyne Dietrich / Bingcan Liu / David Bendahan / Alexander L Perryman / Simon Surprenant / Sara Fournier / Bita Lotfollahzadeh Barzili / Alexanne Bonneau-Fortin / Shou Yun Yin / Marie-Eve Leclaire / Charmi Patel / Hugo Poirier / Sai Save / Yann Mathieu / Nicolas Morin / Claude Godbout / Helen E Burston / Karl E Zahn / Mohamed A Attia / Thomas Pinter / Francis Barabé / Paranjay Parikh / Chandresh Jagani / Gyunghoon Kang / Giovanna Scapin / Yael Mamane / Agnel Sfeir / Pavel Mader / Frank Sicheri / Michal Zimmermann / Anne Roulston / Stephen J Morris / W Cameron Black / Michel Gallant /
PubMed AbstractDNA 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 ...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 or 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 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.
External linksJ Med Chem / PubMed:40920169
MethodsEM (single particle)
Resolution2.67 - 2.9 Å
Structure data

70812

9osw

EMDB-70812, PDB-9osw:
Tetrameric POLQ Helicase-like Domain Bound to Cmpd 19, a Small-Molecule ATPase Inhibitor and Drug Candidate Analog
Method: EM (single particle) / Resolution: 2.67 Å

70813

9osy

EMDB-70813, PDB-9osy:
Tetrameric POLQ Helicase-like Domain Bound to Cmpd 36, a Small-Molecule ATPase Inhibitor and Drug Candidate Analog
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

PDB-1cer:
DETERMINANTS OF ENZYME THERMOSTABILITY OBSERVED IN THE MOLECULAR STRUCTURE OF THERMUS AQUATICUS D-GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE AT 2.5 ANGSTROMS RESOLUTION

PDB-1ceq:
CHLOROQUINE BINDS IN THE COFACTOR BINDING SITE OF PLASMODIUM FALCIPARUM LACTATE DEHYDROGENASE.

Source
  • homo sapiens (human)
KeywordsDNA BINDING PROTEIN / Theta-mediated end-joining DNA-dependent ATPase DNA repair Inhibitor co-complex

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