9OSW

Tetrameric POLQ Helicase-like Domain Bound to Cmpd 19, a Small-Molecule ATPase Inhibitor and Drug Candidate Analog

This is a non-PDB format compatible entry.

Summary for 9OSW

• Entry DOI: 10.2210/pdb9osw/pdb
• EMDB information: 70812
• Descriptor: DNA polymerase theta, (3M)-2'-chloro-N-{5-[(1S,2S)-2-(4-cyanophenyl)cyclopropyl]-1,3,4-thiadiazol-2-yl}-5'-methoxy[3,4'-bipyridine]-4-carboxamide (2 entities in total)
• Functional Keywords: theta-mediated end-joining dna-dependent atpase dna repair inhibitor co-complex, dna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 405495.04

Authors

Zahn, K.E.,Mader, P.,Sicheri, F. (deposition date: 2025-05-26, release date: 2025-09-17, Last modification date: 2025-10-01)

Primary citation

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.,Barabe, 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.
The Discovery of RP-2119: A Potent, Selective, and Orally Bioavailable Pol theta ATPase Inhibitor.
J.Med.Chem., 68:19726-19745, 2025

PubMed 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 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.

PubMed: 40920169
DOI: 10.1021/acs.jmedchem.5c02103

Experimental method

ELECTRON MICROSCOPY (2.67 Å)