Document Type
Article
Publication Date
10-22-2025
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 IC50, 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.
Recommended Citation
Chandramouly, Gurushankar; Fried, William; Gordon, John; Ralph, Douglas; Keuk, Channita; Kumari, Sangeeta; Ramanjulu, Mercy; Auerbacher, William; Minakhin, Leonid; Tredinnick, Taylor; Tiberi, Bernadette; Morton, George; Betsch, Robert; Cai, Kathy Q.; Vekariya, Umeshkumar M; Tyagi, Mrityunjay; Skorski, Tomasz; Karakashev, Sergey; Johnson, Neil; Childers, Wayne E.; Chen, Xiaojiang S.; and Pomerantz, Richard T., "RTx-303, an Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates PARP Inhibitors in BRCA Mutant Tumors" (2025). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 289.
https://jdc.jefferson.edu/bmpfp/289
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
41124685
Language
English
Comments
This article is the author's final published version in the Journal of Medicinal Chemistry, Volume 68, Issue 21, Pages 22196−22215.
The final published version is available at https://doi.org/10.1021/acs.jmedchem.5c00551. Copyright © 2025 The Authors. Published by American Chemical Society.