| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg |
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| 25mg |
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| Targets |
Polθ ( IC50 = 5.8 nM )
RP-6685 targets DNA polymerase theta (Polθ), an enzyme involved in DNA repair pathways, particularly in microhomology-mediated end joining (MMEJ). Polθ is a promising target for cancer therapy because it is upregulated in many cancers and is essential for the survival of cells with defects in homologous recombination repair (HRR). Inhibition of Polθ by RP-6685 leads to accumulation of DNA damage and cell death, particularly in HRR-deficient tumors. |
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| ln Vitro |
RP-6685 is inert against ATPase activity and has an IC50 of 550 pM for pol activity against full-length Polθ [1]. With an IC50 of 0.94 μM, RP-6685 inhibits Polθ in HEK293 LIG4-/-cells[1].
In vitro, RP-6685 demonstrates potent inhibition of DNA polymerase theta (Polθ) with an IC50 of 5.8 nM in the PicoGreen assay. It selectively inhibits Polθ over other DNA polymerases. The compound shows antiproliferative activity in cancer cell lines, particularly those with defects in homologous recombination repair pathways. The mechanism involves inhibition of Polθ-mediated DNA repair, leading to accumulation of DNA double-strand breaks and cell death. |
| ln Vivo |
In BRCA2-deficient HCT116 mice, RP-6685 (80 mg/kg; oral; BID for 21 days) showed strong anti-tumor effectiveness [1].
In vivo, RP-6685 demonstrates antitumor efficacy in mouse tumor transplant models. The compound is orally active and shows significant tumor growth inhibition in various xenograft models. The antitumor effect is attributed to the inhibition of Polθ, which is essential for the survival of HRR-deficient tumor cells. The compound is currently being evaluated in clinical trials for its safety, efficacy, and potential in treating certain cancers and inflammatory diseases. |
| Enzyme Assay |
Non-cellular enzyme/receptor binding assay protocols for RP-6685 involve measuring Polθ inhibition using the PicoGreen assay. The assay typically uses recombinant Polθ enzyme and a DNA substrate. The IC50 is determined by measuring the inhibition of DNA polymerase activity at various concentrations of the compound. Selectivity assays against other DNA polymerases (e.g., Pol α, Pol β, Pol γ, Pol δ, Pol ε) are performed to confirm specificity.
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| Cell Assay |
Cellular assay protocols for RP-6685 involve treating cancer cell lines with the compound. Cells are incubated with various concentrations of RP-6685 for 72-96 hours. Cell viability is assessed using MTT, CellTiter-Glo, or similar assays. DNA damage is measured by γ-H2AX staining. Cell cycle analysis and apoptosis assays are performed to understand the mechanism of action. HRR-deficient cell lines are used to evaluate selective cytotoxicity.
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| Animal Protocol |
Animal/Disease Models: Female CD1 nude mice (HCT116 BRCA2+/+ and BRCA2-/- xenograft tumor models)[1]
Doses: 80 mg/kg Route of Administration: po ; BID for 21 days Experimental Results: demonstrated tumor regression during the first 8 days of treatment in BRCA2-/- HCT116 model, while did not inhibit tumor growth in BRCA2+/+ HCT116 tumors mice. Animal/Disease Models: CD1 mice (20-30 g) [1] Doses: 2.5 mg/kg Route of Administration: iv or po; single dosage Experimental Results: CL (mL/min/kg) Vdss (L/kg) t1/2 (h) F (%) 36.8 1.1 0.4 66 In vivo animal experiment protocols for RP-6685 typically involve subcutaneous tumor xenograft models in immunodeficient mice. The compound is administered orally at various doses, typically once or twice daily. Tumor volume is measured regularly (2-3 times per week) to assess antitumor efficacy. Body weight is monitored for toxicity assessment. At study termination, tumors are collected for PK/PD analysis, including measurement of compound concentrations and assessment of Polθ inhibition and DNA damage markers. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of RP-6685 indicate it is orally active. As a small molecule (MW 497.37 g/mol) with favorable drug-like properties, it shows good oral bioavailability. PK studies typically assess parameters including half-life (t½), maximum concentration (Cmax), time to maximum concentration (Tmax), area under the curve (AUC), clearance (CL), and volume of distribution (Vd) in rodents and other species. The compound is currently in clinical development.
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| Toxicity/Toxicokinetics |
The toxicity profile of RP-6685 is being evaluated in preclinical and clinical studies. Standard toxicological evaluation includes acute and sub-chronic toxicity studies in rodents and non-rodent species, genotoxicity testing (Ames test, micronucleus assay), and cardiovascular safety assessments (hERG channel inhibition). The compound is currently in clinical trials, and safety data are being collected.
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| References | |
| Additional Infomation |
RP-6685 (CAS: 2832047-80-8) has a molecular formula of C22H14F7N5O and a molecular weight of 497.37 g/mol. It is a potent, selective, and orally active inhibitor of DNA polymerase theta (Polθ) with an IC50 of 5.8 nM. RP-6685 demonstrates antitumor efficacy in mouse tumor transplant models. The compound is currently undergoing clinical trials for the treatment of certain cancers and inflammatory diseases. Purity is typically ≥99%. This compound is for research use only.
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| Molecular Formula |
C22H14F7N5O
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|---|---|
| Molecular Weight |
497.37
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| Exact Mass |
497.11
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| Elemental Analysis |
C, 53.13; H, 2.84; F, 26.74; N, 14.08; O, 3.22
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| CAS # |
2832047-80-8
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| PubChem CID |
165413021
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| Appearance |
White to off-white solid powder
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| LogP |
3.2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
35
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| Complexity |
785
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1(CC(N(CC#CC2=NN=C(N)C=C2)C2=CC=C(F)C=C2)=O)=NC=C(C(F)(F)F)C=C1C(F)(F)F
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| InChi Key |
LHFFKHVGAKIDNO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H14F7N5O/c23-14-3-6-16(7-4-14)34(9-1-2-15-5-8-19(30)33-32-15)20(35)11-18-17(22(27,28)29)10-13(12-31-18)21(24,25)26/h3-8,10,12H,9,11H2,(H2,30,33)
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| Chemical Name |
N-[3-(6-aminopyridazin-3-yl)prop-2-ynyl]-2-[3,5-bis(trifluoromethyl)pyridin-2-yl]-N-(4-fluorophenyl)acetamide
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| Synonyms |
RP6685; RP-6685; RP 6685
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~201.1 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.18 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0106 mL | 10.0529 mL | 20.1058 mL | |
| 5 mM | 0.4021 mL | 2.0106 mL | 4.0212 mL | |
| 10 mM | 0.2011 mL | 1.0053 mL | 2.0106 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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