2. Academic Validation
  3. RTx-303, an Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates PARP Inhibitors in BRCA Mutant Tumors

RTx-303, an Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates PARP Inhibitors in BRCA Mutant Tumors

  • J Med Chem. 2025 Nov 13;68(21):22196-22215. doi: 10.1021/acs.jmedchem.5c00551.
Gurushankar Chandramouly 1,  William Fried 2,  John Gordon 3,  Douglas Ralph 1,  Channita Keuk 3,  Sangeeta Kumari 4,  Mercy Ramanjulu 5,  William Auerbacher 1,  Leonid Minakhin 1,  Taylor Tredinnick 1,  Bernadette Tiberi 1,  George Morton 4,  Robert Betsch 6,  Kathy Q Cai 6,  Umeshkumar M Vekariya 3,  Mrityunjay Tyagi 1,  Tomasz Skorski 6 3,  Sergey Karakashev 3,  Neil Johnson 6,  Wayne E Childers Jr 5 4,  Xiaojiang S Chen 2 5,  Richard T Pomerantz 1 5
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, United States.
  • 2 Molecular and Computational Biology, USC Dornsife Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, United States.
  • 3 Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania 19140, United States.
  • 4 Temple University, School of Pharmacy, Philadelphia, Pennsylvania 19140, United States.
  • 5 Recombination Therapeutics, Pennsylvania Biotechnology Center, Doylestown, Pennsylvania 18902, United States.
  • 6 Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, United States.
PMID: 41124685 DOI: 10.1021/acs.jmedchem.5c00551
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.

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