9D6N
Loop-Deleted DNA Polymerase Theta in Complex with a dsDNA Overhang and an Allostertic Inhibitor
This is a non-PDB format compatible entry.
Summary for 9D6N
| Entry DOI | 10.2210/pdb9d6n/pdb |
| Descriptor | DNA polymerase theta, DNA Template, DNA Primer, ... (7 entities in total) |
| Functional Keywords | dna polymerase theta, dna polymerase, allosteric inhibitor, protein-dna complex, dna binding protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 6 |
| Total formula weight | 170622.53 |
| Authors | Fried, W.,Chen, X.S. (deposition date: 2024-08-15, release date: 2025-08-20, Last modification date: 2026-03-04) |
| Primary citation | Chandramouly, G.,Fried, W.,Gordon, J.,Ralph, D.,Keuk, C.,Kumari, S.,Ramanjulu, M.,Auerbacher, W.,Minakhin, L.,Tredinnick, T.,Tiberi, B.,Morton, G.,Betsch, R.,Cai, K.Q.,Vekariya, U.M.,Tyagi, M.,Skorski, T.,Karakashev, S.,Johnson, N.,Childers Jr., W.E.,Chen, X.S.,Pomerantz, R.T. RTx-303, an Orally Bioavailable Pol theta Polymerase Inhibitor That Potentiates PARP Inhibitors in BRCA Mutant Tumors. J.Med.Chem., 68:22196-22215, 2025 Cited by PubMed Abstract: DNA polymerase θ (Polθ) is a polymerase-helicase fusion protein that is synthetically lethal with homologous recombination (HR) factors, such as BRCA1/2, and confers resistance to PARP inhibitors (PARPi) and other genotoxic cancer therapies. Previously developed Polθ polymerase (Polθ-pol) inhibitors (Polθi) exhibited limited pharmacological activity and metabolic stability, warranting the development of a Polθi with improved drug-like properties. Here, we developed RTx-303, a selective allosteric small-molecule Polθ-pol inhibitor that exhibits 5.1 nM IC, 88% oral bioavailability, and a prolonged half-life along with its equipotent metabolite. X-ray crystallography highlights the development of a solvent-exposed side-chain that is essential for the optimal drug-like properties of RTx-303. Notably, RTx-303 exhibits significantly higher cellular potency than previously developed Polθ-pol inhibitors and strongly potentiates PARPi in BRCA1/2 mutant cells and patient-derived xenograft models. The superior potency, robust pharmacological activity, and high tolerability of RTx-303 warrant further development as a Polθ-pol inhibitor drug candidate. PubMed: 41124685DOI: 10.1021/acs.jmedchem.5c00551 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.43 Å) |
Structure validation
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