RTx-303, an Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates PARP Inhibitors in BRCA Mutant Tumors
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<sub>50</sub>, 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.
Authors
- William Fried
- Taylor Tredinnick (ORCID: https://orcid.org/0000-0002-0106-5194)
- Xiaojiang S. Chen (ORCID: https://orcid.org/0000-0001-9574-0551)
- Mrityunjay Tyagi
- Gurushankar Chandramouly
- Mercy Ramanjulu
- Neil Johnson (ORCID: https://orcid.org/0000-0002-0276-0009)
- Leonid Minakhin (ORCID: https://orcid.org/0000-0003-0301-7054)
- Wayne E. Childers (ORCID: https://orcid.org/0000-0003-0527-3684)
- Sergey Karakashev (ORCID: https://orcid.org/0000-0002-9849-2714)
- Tomasz Skórski (ORCID: https://orcid.org/0000-0002-3809-4538)
- John Gordon (ORCID: https://orcid.org/0000-0001-8191-2156)
- Sangeeta Kumari (ORCID: https://orcid.org/0000-0003-1206-1655)
- Kathy Q. Cai (ORCID: https://orcid.org/0000-0002-6034-3377)
- Richard T. Pomerantz (ORCID: https://orcid.org/0000-0003-1194-9871)
- George Morton
- Robert Betsch
- Bernadette Tiberi
- William Auerbacher
- Douglas Ralph
- Umeshkumar M. Vekariya
- Channita Keuk
Institutions
- University of Southern California (US)
- Fox Chase Cancer Center (US)
- Thomas Jefferson University (US)
- California Southern University (US)
- Temple College (US)
- Biotechnology Research Center (IR)
- Recombinant Technologies (United States) (US)
- Center for Personalized Cancer Treatment (NL)
- Sidney Kimmel Cancer Center (US)
- Dynamique du noyau (FR)
- Temple University (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-10-22
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00551
- Citations
- 2
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.61