TY - JOUR
T1 - RTx-303, an Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates PARP Inhibitors in BRCA Mutant Tumors
AU - Chandramouly, Gurushankar
AU - Fried, William
AU - Gordon, John
AU - Ralph, Douglas
AU - Keuk, Channita
AU - Kumari, Sangeeta
AU - Ramanjulu, Mercy
AU - Auerbacher, William
AU - Minakhin, Leonid
AU - Tredinnick, Taylor
AU - Tiberi, Bernadette
AU - Morton, George
AU - Betsch, Robert
AU - Cai, Kathy Q.
AU - Vekariya, Umeshkumar M.
AU - Tyagi, Mrityunjay
AU - Skorski, Tomasz
AU - Karakashev, Sergey
AU - Johnson, Neil
AU - Childers, Wayne E.
AU - Chen, Xiaojiang S.
AU - Pomerantz, Richard T.
N1 - Publisher Copyright:
© 2025 The Authors. Published by American Chemical Society
PY - 2025/11/13
Y1 - 2025/11/13
N2 - 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
50, 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.
AB - 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
50, 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.
KW - Administration, Oral
KW - Animals
KW - Antineoplastic Agents/pharmacology
KW - BRCA1 Protein/genetics
KW - BRCA2 Protein/genetics
KW - Biological Availability
KW - Cell Line, Tumor
KW - Crystallography, X-Ray
KW - DNA Polymerase theta
KW - DNA-Directed DNA Polymerase/metabolism
KW - Enzyme Inhibitors/pharmacology
KW - Female
KW - Humans
KW - Mice
KW - Mutation
KW - Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
KW - Rats
KW - Structure-Activity Relationship
KW - Xenograft Model Antitumor Assays
UR - https://www.scopus.com/pages/publications/105021427014
U2 - 10.1021/acs.jmedchem.5c00551
DO - 10.1021/acs.jmedchem.5c00551
M3 - Article
C2 - 41124685
SN - 0022-2623
VL - 68
SP - 22196
EP - 22215
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 21
ER -
