2. Cell Cycle/DNA Damage Epigenetics
  3. PARP
  4. RK-582

RK-582 is a tankyrase inhibitor, antitumor agent, and orally bioavailable growth inhibitor, with an IC50 of 36.1 nM against human tankyrase-1 and an IC50 of 39.2 nM against human tankyrase-2. In APC-mutated colorectal cancer cells, the sensitivity to RK-582 correlates with the level of active β-catenin, while drug resistance associates with PIK3CA mutation. RK-582 can be used for the research of colorectal cancer.

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RK-582

RK-582 Chemical Structure

CAS No. : 2171388-28-4

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Based on 1 publication(s) in Google Scholar

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Description

RK-582 is a tankyrase inhibitor, antitumor agent, and orally bioavailable growth inhibitor, with an IC50 of 36.1 nM against human tankyrase-1 and an IC50 of 39.2 nM against human tankyrase-2. In APC-mutated colorectal cancer cells, the sensitivity to RK-582 correlates with the level of active β-catenin, while drug resistance associates with PIK3CA mutation. RK-582 can be used for the research of colorectal cancer[1][2].

IC50 & Target

IC50: 36.1 nM (TNKS1/PARP5A), 18.168 nM (PARP1)[1]
Cellular Effect
Cell Line Type Value Description References
COLO 320 GI50
230 nM
Compound: 35; RK-582
Antiproliferative activity against human COLO 320 assessed as growth inhibition measured after 24 hrs
Antiproliferative activity against human COLO 320 assessed as growth inhibition measured after 24 hrs
[PMID: 33822624]
COLO 320DM GI50
0.035 μM
Compound: 41g; RK-582
Antiproliferative activity against human COLO320DM cells assessed inhibition of cell growth measured after 5 days by MTT assay
Antiproliferative activity against human COLO320DM cells assessed inhibition of cell growth measured after 5 days by MTT assay
[PMID: 32202790]
COLO 320DM GI50
0.23 μM
Compound: 41g; RK-582
Antiproliferative activity against human COLO320DM cells assessed as inhibition of cell growth measured after 4 days by CellTiter-Glo assay
Antiproliferative activity against human COLO320DM cells assessed as inhibition of cell growth measured after 4 days by CellTiter-Glo assay
[PMID: 32202790]
HEK293 IC50
0.3 nM
Compound: 41g; RK-582
Inhibition of TNKS/TNKS2 (unknown origin) expressed in HEK293 cells assessed as reduction in Wnt-signaling measured after 24 hrs by TCF-luciferase reporter gene assay
Inhibition of TNKS/TNKS2 (unknown origin) expressed in HEK293 cells assessed as reduction in Wnt-signaling measured after 24 hrs by TCF-luciferase reporter gene assay
[PMID: 32202790]
RKO GI50
> 10 μM
Compound: 41g; RK-582
Antiproliferative activity against human RKO cells assessed inhibition of cell growth measured after 5 days by MTT assay
Antiproliferative activity against human RKO cells assessed inhibition of cell growth measured after 5 days by MTT assay
[PMID: 32202790]
Sf9 IC50
1240 nM
Compound: 41g; RK-582
Inhibition of human recombinant N-terminal GST-tagged PARP2 (2 to 583 residues) expressed in baculovirus infected Sf9 cells assessed as reduction in auto-PARylation using histone as substrate measured after 45 mins in presence of biotinylated-NAD+ by ELISA
Inhibition of human recombinant N-terminal GST-tagged PARP2 (2 to 583 residues) expressed in baculovirus infected Sf9 cells assessed as reduction in auto-PARylation using histone as substrate measured after 45 mins in presence of biotinylated-NAD+ by ELISA
[PMID: 32202790]
In Vitro

RK-582 (0.001-1 μM; 5 days) exhibits high or intermediate sensitivity in short APC-mutated CRC PDCs, while long APC-mutated CRC PDCs show variable sensitivity; RK-582 sensitivity negatively correlates with active β-catenin levels in both overall and long APC-type CRC PDCs[1].
RK-582 (0.3 μM; 24 h) induces AXIN2 accumulation and reduces active β-catenin levels in short APC-mutated CRC PDCs, but does not alter active β-catenin in resistant long APC-mutated CRC PDCs[1].
RK-582 (0.3 μM; 24 h) induces AXIN1 accumulation without altering active β-catenin in APC-wild type CRC PDCs JC-11 and JC-494; at 3 μM, 24 h, it modulates MYC and E2F-related cell cycle regulators in these cells[1].
RK-582 (0.001-10 μM; 5 days for proliferation assay; 3 μM, 48 h for WB) anti-proliferative effect on APC-wild type CRC PDC JC-11 is partially dependent on p21 induction, as siRNA-mediated p21 knockdown reduces RK-582's growth inhibitory activity[1].
RK-582 (range; 10 min pre-incubation, 45 min reaction) potently inhibits human tankyrase-1 and tankyrase-2 catalytic activity, with ~504-fold selectivity over PARP1, ~34-fold selectivity over PARP2, and ~223-fold selectivity over PARP10[2].
RK-582 (range) potently inhibits Wnt/β-catenin signaling in HEK293 and DLD-1 cells, with stronger activity in HEK293 cells[2].
RK-582 (range; 4 days) potently inhibits the growth of COLO-320DM human colorectal cancer cells with a half-maximal growth inhibition concentration of 0.23 μM[2].
RK-582 (range; 5 days) potently inhibits the proliferation of β-catenin-dependent COLO-320DM colorectal cancer cells (GI50 = 0.035 μM) but does not affect β-catenin-independent RKO cells[2].
RK-582 (0.1 μM; 16 h) modulates Wnt/β-catenin signaling in COLO-320DM cells by stabilizing AXIN2, reducing active β-catenin, and preventing tankyrase degradation[2].
RK-582 (1 mM; 7 days soaking) binds to human TNKS2 via multiple specific interactions within the nicotinamide binding pocket, with the 2,6-dimethylmorpholine group oriented toward the cytosolic space[2].

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

RK-582 Related Antibodies

Cell Proliferation Assay[1]

Cell Line: colorectal cancer (CRC) patient-derived cells (PDCs): expanded cohort of 26 APC-mutated cells, combined cohort of 42 APC-mutated cells, 16 short APC PDCs, 26 long APC PDCs (16 sensitive/intermediate, 10 resistant)
Concentration: 0.001-1 μM; 1 μM
Incubation Time: 5 days
Result: Exhibited high or intermediate sensitivity in all 16 short APC PDCs. Showed variable sensitivity in long APC PDCs, with 16 samples sensitive/intermediate and 10 samples resistant. Showed a strong positive correlation with sensitivity to G007-LK (Pearson’s correlation score R = 0.85) at 1 μM for 5 days. Negatively correlated with active β-catenin levels (Pearson’s correlation score R = -0.42) in the combined cohort of 42 APC-mutated PDCs, and R = -0.43 in long APC-type PDCs.

Western Blot Analysis[1]

Cell Line: short APC (JC-21, JC-73) and long APC resistant (JC-63) CRC PDCs
Concentration: 0.3 μM
Incubation Time: 24 h
Result: Caused AXIN2 protein accumulation and decreased levels of active β-catenin in short APC PDCs JC-21 and JC-73. Had no effect on active β-catenin levels in resistant long APC PDC JC-63.

Western Blot Analysis[1]

Cell Line: APC-wild type CRC PDCs (JC-11, JC-494)
Concentration: 0.3 μM; 3 μM
Incubation Time: 24 h
Result: Induced accumulation of AXIN1 (but not AXIN2) and did not significantly reduce active β-catenin levels in JC-11 and JC-494 cells. Reduced MYC protein levels, reduced phosphorylated RB (Ser807/811) and cyclin D1 levels, and upregulated p21 protein levels in JC-11 cells. Did not alter MYC levels in JC-494 cells.

Cell Proliferation Assay[2]

Cell Line: Human colorectal cancer COLO-320DM cells, human colorectal cancer RKO cells
Concentration: Range (to determine GI50 values)
Incubation Time: 5 days
Result: Demonstrated a GI50 of 0.035 μM in COLO-320DM cells and showed no growth inhibition (GI50 >10 μM) in β-catenin-independent RKO cells.

Western Blot Analysis[2]

Cell Line: Human colorectal cancer COLO-320DM cells
Concentration: 0.1 μM
Incubation Time: 16 h
Result: Induced a 7.78-fold upregulation of AXIN2 protein levels and reduced active β-catenin protein levels to 0.39 relative to DMSO control. Upregulated tankyrase protein levels.
Parmacokinetics
Species Dose Route Cmax Tmax T1/2
Mice[2] 50 mg/kg i.p. 102 μM 1 h 1.9 h
Mice[2] 50 mg/kg p.o. 121 μM 1 h 1.8 h
Mice[2] 20 mg/kg i.p. 75.6 μM 1 h 2.8 h
Mice[2] 20 mg/kg p.o. 76.6 μM 1 h 1.7 h
In Vivo

RK-582 (5-20 mg/kg; i.p.; per study schedule) produces dose-dependent, tolerable antitumor efficacy in short APC mutant COLO-320DM colorectal cancer xenografts in female NOD.CB17-Prkdcscid/J mice, with confirmed on-target tankyrase inhibition[1].
RK-582 (20 mg/kg; i.p.; per study schedule) shows no antitumor efficacy in resistant long APC mutant HCT-15 colorectal cancer xenografts in female BALB/c-nu/nu mice, even with confirmed on-target tankyrase inhibition[1].
RK-582 (10-20 mg/kg; i.p.; twice daily; 5-day on/2-day off, 2 weeks) administered intraperitoneally achieves 68.8% and 71.1% tumor growth inhibition, respectively, in a COLO-320DM xenograft model without inducing observable toxicity[2].
RK-582 (10-20 mg/kg; p.o.; twice daily; 5-day on/2-day off, 2 weeks) administered orally achieves 52.3% and 52.0% tumor growth inhibition, respectively, in a COLO-320DM xenograft model without inducing observable toxicity, and modulates Wnt/β-catenin pathway biomarkers in tumor tissues[2].

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

Animal Model: NOD.CB17-Prkdcscid/J (6-week-old female, subcutaneous xenograft of COLO-320DM cells)[1]
Dosage: 5 mg/kg; 20 mg/kg
Administration: i.p.; per study schedule
Result: Exhibited dose-dependent antitumor effects under tolerable dosing. Sufficiently inhibited tankyrase enzymes in tumors, as shown by AXIN2 accumulation.
Animal Model: BALB/c-nu/nu (5-week-old female, subcutaneous xenograft of HCT-15 cells)[1]
Dosage: 20 mg/kg
Administration: i.p.; per study schedule
Result: Did not exhibit antitumor effects under tolerable dosing. Sufficiently inhibited tankyrase enzymes in tumors via AXIN2 accumulation.
Animal Model: NOD.CB17-Prkdcscid/J (female, 6-week-old, subcutaneous xenograft with COLO-320DM cells)[2]
Dosage: 10 mg/kg; 20 mg/kg
Administration: i.p.; twice daily; 5-day on/2-day off, 2 weeks
Result: Achieved 68.8% tumor growth inhibition at 10 mg/kg twice daily.
Achieved 71.1% tumor growth inhibition at 20 mg/kg twice daily.
Elevated cytosolic AXIN2 levels in tumor tissues.
Showed no reduction in active β-catenin and total β-catenin levels in nuclear extracts compared to controls.
Caused no meaningful weight loss or unusual behaviors in treated mice.
Animal Model: NOD.CB17-Prkdcscid/J (female, 6-week-old, subcutaneous xenograft with COLO-320DM cells)[2]
Dosage: 10 mg/kg; 20 mg/kg
Administration: p.o.; twice daily; 5-day on/2-day off, 2 weeks
Result: Achieved 52.3% tumor growth inhibition at 10 mg/kg twice daily.
Achieved 52.0% tumor growth inhibition at 20 mg/kg twice daily.
Elevated cytosolic AXIN2 levels in tumor tissues.
Reduced active β-catenin and total β-catenin levels in nuclear extracts compared to controls.
Reached plasma concentration of 10.1 μmol/L at 4-hour time point on day 12 in 10 mg/kg twice daily group.
Reached plasma concentration of 23.3 μmol/L at 4-hour time point on day 12 in 20 mg/kg twice daily group.
Caused no meaningful weight loss or unusual behaviors in treated mice.
Molecular Weight

510.60

Formula

C27H35FN6O3
CAS No.
Appearance

Solid

Color

White to off-white

SMILES

O=C(N1C)C2(CCN(C(NC3=C4CCCN3C)=NC4=O)CC2)C(C1=CC(N(C[C@@H]5C)C[C@H](O5)C)=C6)=C6F
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 : 25 mg/mL (48.96 mM; ultrasonic and warming and heat to 60°C; 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 1.9585 mL 9.7924 mL 19.5848 mL
5 mM 0.3917 mL 1.9585 mL 3.9170 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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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: ≥ 2.5 mg/mL (4.90 mM); Clear solution

    This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).

    Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 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: ≥ 2.5 mg/mL (4.90 mM); Clear solution

    This protocol yields a clear solution of ≥ 2.5 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 (25.0 mg/mL) to 900 μL Corn oil, and mix evenly.

In Vivo Dissolution Calculator
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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:
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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 1.9585 mL 9.7924 mL 19.5848 mL 48.9620 mL
5 mM 0.3917 mL 1.9585 mL 3.9170 mL 9.7924 mL
10 mM 0.1958 mL 0.9792 mL 1.9585 mL 4.8962 mL
15 mM 0.1306 mL 0.6528 mL 1.3057 mL 3.2641 mL
20 mM 0.0979 mL 0.4896 mL 0.9792 mL 2.4481 mL
25 mM 0.0783 mL 0.3917 mL 0.7834 mL 1.9585 mL
30 mM 0.0653 mL 0.3264 mL 0.6528 mL 1.6321 mL
40 mM 0.0490 mL 0.2448 mL 0.4896 mL 1.2241 mL
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Keywords:

RK-5822171388-28-4RK582RK 582PARPpoly ADP ribose polymeraseβ-cateninMYCtankyrase-1E2FWnt/β-catenin signalingtankyrase-2AXIN2AXIN proteinsCOLO-320DMcolorectal cancer cellsInhibitorinhibitorinhibit

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