2. Cell Cycle/DNA Damage
  3. DNA/RNA Synthesis
  4. RP-2119

RP-2119 is an orally bioactive Polymerase Theta (Polθ) inhibitor, with an IC50 of 0.7 nM against human Polθ ATPase. RP-2119 reduces Polθ activity and exerts antiproliferative effects in BRCA2-deficient cancer cells. RP-2119 exhibits antitumor activity in BRCA2-deficient cancer cell xenograft mouse models. RP-2119 can be used for the research of cancer and homologous recombination-deficient cancers, including brca1/brca2-mutant cancers and shld2-mutant cancers.

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RP-2119

RP-2119 Chemical Structure

CAS No. : 2922287-81-6

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RP-2119 Related Antibodies

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Description

RP-2119 is an orally bioactive Polymerase Theta (Polθ) inhibitor, with an IC50 of 0.7 nM against human Polθ ATPase. RP-2119 reduces Polθ activity and exerts antiproliferative effects in BRCA2-deficient cancer cells. RP-2119 exhibits antitumor activity in BRCA2-deficient cancer cell xenograft mouse models. RP-2119 can be used for the research of cancer and homologous recombination-deficient cancers, including brca1/brca2-mutant cancers and shld2-mutant cancers[1][2].

In Vitro

RP-2119 potently inhibits human Polθ ATPase activity in the ADP-Glo biochemical assay, with an IC50 of 0.7 nM. It also inhibits Polθ ATPase activity in mice, rats, dogs, pigs and chimpanzees, with IC50 values ranging from <1.5 nM to <5 nM in the ADP-Glo biochemical assay[2].
RP-2119 binds to Polθ in K562 cells expressing the ePL-tagged Flag-Polθ helicase domain, with an EC50 of 82 nM in the CETSA assay[2].
RP-2119 (for 12-14 days) potently inhibits the proliferation of DLD-1, HCT 116 and DOTC24510 BRCA2-/- cells, with EC50 values of 45, 51 and 266 nM[2].
RP-2119 inhibits Polθ-mediated MMEJ activity in DLD-1 cells carrying Cas9/sgRNA-induced double-strand breaks at the AAVS1 locus, with an IC50 of 54 nM[2].

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

RP-2119 Related Antibodies
Parmacokinetics
Species Dose Route CL Vdss T1/2 Bioavailability
Mice[2] 1 mg/kg i.v. 5.0 mL/min/kg 0.54 L/kg 2.1 h /
Mice[2] 2.5 mg/kg p.o. / / / 47 %
Rat[2] 0.5 mg/kg i.v. 0.54 mL/min/kg 0.18 L/kg 5.7 h /
Rat[2] 2.5 mg/kg p.o. / / / 36 %
Dog[2] 0.5 mg/kg i.v. 0.13 mL/min/kg 0.16 L/kg 11.0 h /
Dog[2] 1.25 mg/kg p.o. / / / 103 %
Cynomolgus Monkey[2] 0.5 mg/kg i.v. 2.1 mL/min/kg 0.67 L/kg 8.1 h /
Cynomolgus Monkey[2] 1.25 mg/kg p.o. / / / 84 %
In Vivo

RP-2119 (Compound 113) (0-300 mg/kg; p.o.; once/twice daily; throughout the entire study period/24 days) induces dose-dependent tumor growth inhibition in a mouse HCT116 BRCA2-/- colorectal cancer model, with a maximum inhibition rate of 53%, and enhances the tumor volume reduction effect of Olaparib (HY-10162)[1][2].
RP-2119 (45 mg/kg; p.o.; once daily; for the entire study duration) enhances the tumor volume reduction effect of Carboplatin (HY-17393) in a mouse DLD1 BRCA2-/- colorectal cancer model[1][2].
Combination treatment with RP-2119 (45 mg/kg; p.o.; twice daily; up to 50 days) and Olaparib induces tumor regression in the BRCA2-mutant mouse HBCx-10 breast cancer PDX model, with significantly enhanced efficacy compared to Olaparib monotherapy[2].

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

Animal Model: SCID-Beige (subcutaneous injection of HCT116 BRCA2-/- cells)[1]
Dosage: 30 mg/kg/45 mg/kg; 150 mg/kg; 300 mg/kg
Administration: p.o.; QD; throughout the study/p.o.; BID; 24 days
Result: Produced a superior reduction in tumor volume when combined with olaparib (25 mg/kg p.o.
QD) compared to either agent alone.
Showed a statistically significant difference relative to controls.
Induced 34% tumor growth inhibition (TGI) at 45 mg/kg dose after 24 days of treatment.
Induced 48% TGI at 150 mg/kg dose after 24 days of treatment.
Induced 53% TGI at 300 mg/kg dose after 24 days of treatment.
Was well tolerated with no clinical signs or body weight loss relative to vehicle-treated mice.
Animal Model: SCID-Beige (subcutaneous injection of DLD1 BRCA2-/- cells)[1]
Dosage: 45 mg/kg
Administration: p.o.; QD; throughout the study
Result: Produced a superior reduction in tumor volume when combined with carboplatin (25 mg/kg i.p.
QW) compared to either monotherapy treatment.
Showed a statistically significant difference relative to vehicle plus carboplatin at day 35.
Animal Model: athymic nude (female, 5-9 weeks old)[2]
Dosage: 45 mg/kg (monotherapy); 45 mg/kg (in combination with olaparib 25 mg/kg)
Administration: p.o.; BID; up to 50 days
Result: Induced tumor growth inhibition as monotherapy.
Resulted in tumor regressions and statistically significant improved efficacy compared to olaparib alone when administered in combination with olaparib.
Molecular Weight

507.52

Formula

C24H19F2N7O2S
CAS No.
Appearance

Solid

Color

Off-white to yellow

SMILES

O=C(C1=C(C=C(N=C1)C2=NN(C=C2)C)C3=CC(C(F)F)=NC=C3OC)NC4=NN=C(S4)C#CC5CC5
Shipping

Room temperature in continental US; may vary elsewhere.
Storage
Powder -20°C 3 years
4°C 2 years
In solvent -80°C 6 months
-20°C 1 month
Solvent & Solubility
In Vitro: 

DMSO : 100 mg/mL (197.04 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)

Preparing
Stock Solutions
Concentration Solvent Mass 1 mg 5 mg 10 mg
1 mM 1.9704 mL 9.8518 mL 19.7037 mL
5 mM 0.3941 mL 1.9704 mL 3.9407 mL
View the Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

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Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)

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Concentration (start) × Volume (start) = Concentration (final) × Volume (final)

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In Vivo:

Select the appropriate dissolution method based on your experimental animal and administration route.

For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for in vivo experiments, it is recommended to prepare freshly and use it on the same day.
The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.

  • Protocol 1

    Add each solvent one by one:  10% DMSO    40% PEG300    5% Tween-80    45% Saline

    Solubility: ≥ 5 mg/mL (9.85 mM); Clear solution

    This protocol yields a clear solution of ≥ 5 mg/mL (saturation unknown).

    Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (50.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.

    Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
  • Protocol 2

    Add each solvent one by one:  10% DMSO    90% Corn Oil

    Solubility: ≥ 5 mg/mL (9.85 mM); Clear solution

    This protocol yields a clear solution of ≥ 5 mg/mL (saturation unknown). If the continuous dosing period exceeds half a month, please choose this protocol carefully.

    Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (50.0 mg/mL) to 900 μL Corn oil, and mix evenly.

In Vivo Dissolution Calculator
Please enter the basic information of animal experiments:

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Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
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Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Calculation results:
Working solution concentration: mg/mL
Method for preparing stock solution: mg drug dissolved in μL  DMSO (Stock solution concentration: mg/mL).
The concentration of the stock solution you require exceeds the measured solubility. The following solution is for reference only. If necessary, please contact MedChemExpress (MCE).
Method for preparing in vivo working solution for animal experiments: Take μL DMSO stock solution, add μL . μL , mix evenly, next add μL Tween 80, mix evenly, then add μL Saline.
 If the continuous dosing period exceeds half a month, please choose this protocol carefully.
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
Purity & Documentation
References

Complete Stock Solution Preparation Table

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.

Optional Solvent Concentration Solvent Mass 1 mg 5 mg 10 mg 25 mg
DMSO 1 mM 1.9704 mL 9.8518 mL 19.7037 mL 49.2591 mL
5 mM 0.3941 mL 1.9704 mL 3.9407 mL 9.8518 mL
10 mM 0.1970 mL 0.9852 mL 1.9704 mL 4.9259 mL
15 mM 0.1314 mL 0.6568 mL 1.3136 mL 3.2839 mL
20 mM 0.0985 mL 0.4926 mL 0.9852 mL 2.4630 mL
25 mM 0.0788 mL 0.3941 mL 0.7881 mL 1.9704 mL
30 mM 0.0657 mL 0.3284 mL 0.6568 mL 1.6420 mL
40 mM 0.0493 mL 0.2463 mL 0.4926 mL 1.2315 mL
50 mM 0.0394 mL 0.1970 mL 0.3941 mL 0.9852 mL
60 mM 0.0328 mL 0.1642 mL 0.3284 mL 0.8210 mL
80 mM 0.0246 mL 0.1231 mL 0.2463 mL 0.6157 mL
100 mM 0.0197 mL 0.0985 mL 0.1970 mL 0.4926 mL
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RP-2119 Related Classifications

Help & FAQs
  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

RP-21192922287-81-6RP2119RP 2119DNA/RNA SynthesisBRCA2-deficient cancer cellsPolθ ATPase domainK562 cellscolorectal cancer xenograftsPolymerase ThetaCaco-2 cell monolayersmicrohomology-mediated end joiningDLD-1 BRCA2-/- cellsHCT 116 BRCA2-/- cellsHR-deficient modelsInhibitorinhibitorinhibit

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