RTx-161 

RTx-161 is a DNA polymerase θ inhibitor with an IC₅₀ of 4.1 nM. RTx-161 induces DNA damage, PARP cleavage, apoptosis, and selectively kills homologous recombination-deficient (HRD) cells. RTx-161 acts synergistically with PARP inhibitors to suppress PARP inhibitor resistance in cancer cells. RTx-161 can be used for the research of BRCA^G12C mutant cancer and HR-deficient cancers^[1][2].

RTx-161 (1 μM; 60 min) has poor metabolic stability in mouse CD1 male liver microsomes, with a half-life of <2 min^[1].
RTx-161 (10-12 day) selectively inhibits colony formation in BRCA2^-/^- HCT116 cells with an IC₅₀ of 1.4 μM, while having minimal effect on BRCA2⁺/⁺ HCT116 cells (IC₅₀ >8 μM)^[1].
RTx-161 binds to an allosteric pocket of PolθΔL in complex with DNA and ddGTP, forming specific hydrophobic and hydrogen bond interactions, with a structure resolved to 3.31 Å resolution^[1].
RTx-161 (4-500 nM; 15 min) concentration-dependently inhibits recombinant human Polθ-pol MMEJ activity in a cell-free in vitro assay, with maximal inhibition at 500 nM^[2].
RTx-161 (2 μM; 0-40 min) does not significantly inhibit recombinant human Polθ-pol ddCMP incorporation on open-conformation DNA/RNA primer-templates in a cell-free assay^[2].
RTx-161 (Varying concentrations up to 16 μM; 10-12 days) selectively reduces the survival of HR-deficient cell lines (BRCA2-null DLD1, BRCA2-null HCT116, PALB2-mutant EUFA1341, Brca1^cc/cc MEFs) in clonogenic assays, with minimal effect on HR-proficient controls^[2].
RTx-161 (20 μM; 16 h) suppresses MMEJ repair of site-specific DSBs in U2OS cells expressing a chromosomal GFP reporter cassette^[2].
RTx-161 selectively induces DNA damage (measured by γ-H2AX foci and protein levels) in BRCA2-null DLD1 cells, with minimal effect on BRCA2-WT DLD1 cells^[2].
RTx-161 selectively induces apoptosis (measured by PARP cleavage) in BRCA2-null DLD1 cells, with no significant effect on BRCA2-WT DLD1 cells^[2].
RTx-161 (0.5-10 μM; 10-12 days) acts synergistically with PARP inhibitors (Olaparib (HY-10162), Rucaparib (HY-10617A), Talazoparib (HY-16106)) to reduce survival of HR-deficient cell lines (BRCA2-null HCT116, BRCA2-null DLD1, PE01, VC8, CAPAN-1) and modestly potentiates Talazoparib activity in HR-proficient MDA-MB-231 cells in clonogenic assays^[2].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

509.37

C₂₁H₁₈F₇N₃O₄

3035072-49-9

Solid

Colorless to off-white

FC(F)(F)C1=CC(N2CCN(CCO)C2=O)=C(OC(N(C3=CC=C(F)C=C3)C)=O)C(C(F)(F)F)=C1

Room temperature in continental US; may vary elsewhere.

4°C, protect from light

*In solvent : -80°C, 6 months; -20°C, 1 month (protect from light)

• [1]. Chandramouly G, et al. RTx-303, an Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates PARP Inhibitors in BRCA Mutant Tumors. J Med Chem. 2025;68(21):22196-22215.  [Content Brief]

  [2]. Fried W, et al. Discovery of a small-molecule inhibitor that traps Polθ on DNA and synergizes with PARP inhibitors. Nat Commun. 2024;15(1):2862. Published 2024 Apr 5.  [Content Brief]