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

RK-582 是一种端锚聚合酶抑制剂、抗肿瘤剂及具有口服生物利用度的生长抑制剂，对人 端锚聚合酶-1 (tankyrase-1) 的 IC50 为 36.1 nM，对人 端锚聚合酶-2 (tankyrase-2) 的 IC50 为 39.2 nM。RK-582 在 APC 突变的结直肠癌细胞中，其敏感性与活性 β-catenin 水平相关，耐药性则与 PIK3CA 突变有关。RK-582 可用于结直肠癌的研究。

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RK-582

RK-582 Chemical Structure

CAS No. : 2171388-28-4

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10 mM * 1 mL in DMSO ￥16288
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1 mg ￥5800
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RK-582 相关抗体

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  • 生物活性

  • 纯度 & 产品资料

  • 参考文献

生物活性

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]
细胞效力
(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]
体外研究
(In Vitro)

RK-582 (0.001-1 μM；5 天) 在短型 APC 突变结直肠癌患者来源类器官 (PDCs) 中表现出高或中等敏感性，而长型 APC 突变结直肠癌 PDCs 则表现出敏感性差异；在所有 APC 型以及长型 APC 型结直肠癌 PDCs 中，RK-582 的敏感性与活化 β-catenin 水平呈负相关[1]。
RK-582 (0.3 μM; 24 h) 可在携带 APC 突变的短期结直肠癌类器官 (CRC PDCs) 中诱导 AXIN2 积累并降低活性 β-连环蛋白水平，但在具有耐药性的携带 APC 突变的长期结直肠癌类器官中不会改变活性 β-连环蛋白的水平[1]。
RK-582 (0.3 μM; 24 h) 可在 APC 野生型结直肠癌患者来源类器官 (PDC) JC-11 和 JC-494 中诱导 AXIN1 积累，且不改变活性 β-连环蛋白；在 3 μM、24 h 处理条件下，该化合物可调控上述细胞中与 MYC 和 E2F 相关的细胞周期调控因子[1]。
RK-582 (0.001-10 μM；增殖实验处理 5 天；蛋白质免疫印迹实验处理条件为 3 μM、48 h) 对 APC 野生型结直肠癌患者来源类器官 JC-11 的抗增殖作用部分依赖于 p21 的诱导，因为 siRNA 介导的 p21 敲低会降低 RK-582 的生长抑制活性[1]。
RK-582 (范围；预孵育 10 min，反应 45 min) 可强效抑制人端锚聚合酶-1 (tankyrase-1) 和端锚聚合酶-2 (tankyrase-2) 的催化活性，对 PARP1 的选择性约为 504 倍，对 PARP2 的选择性约为 34 倍，对 PARP10 的选择性约为 223 倍[2]。
RK-582 (一种系列浓度) 可强效抑制 HEK293 和 DLD-1 细胞中的 Wnt/β-catenin 信号通路，且在 HEK293 细胞中的活性更强[2]。
RK-582 (4 天) 可强效抑制人结直肠癌细胞 COLO-320DM 的增殖，其半数增殖抑制浓度 (IC50) 为 0.23 μM[2]。
RK-582 (给药周期：5 天) 可强效抑制 β-连环蛋白 (β-catenin) 依赖型结直肠癌细胞 COLO-320DM 的增殖 (GI50 = 0.035 μM)，但对 β-连环蛋白非依赖型 RKO 细胞无影响[2]。
RK-582 (0.1 μM; 16 h) 可通过稳定 AXIN2、减少活性 β-catenin 并抑制端锚聚合酶降解，来调控 COLO-320DM 细胞中的 Wnt/β-catenin 信号通路[2]。
RK-582 (1 mM； 7 天) 可通过烟酰胺结合口袋内的多个特异性相互作用与人类 TNKS2 结合，其 2,6-二甲基吗啉基团朝向胞质空间[2]。

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

RK-582 相关抗体:

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.
药代动力学
(Parmacokinetics)
Species Dose Route Indicator value
Mice 50 mg/kg i.p. Tmax 1 h
Mice 50 mg/kg i.p. Cmax 102 μM
Mice 50 mg/kg i.p. T1/2 1.9 h
Mice 50 mg/kg p.o. Tmax 1 h
Mice 50 mg/kg p.o. Cmax 121 μM
Mice 50 mg/kg p.o. T1/2 1.8 h
Mice 20 mg/kg i.p. Cmax 75.6 μM
Mice 20 mg/kg i.p. Tmax 1 h
Mice 20 mg/kg i.p. T1/2 2.8 h
Mice 20 mg/kg p.o. Cmax 76.6 μM
Mice 20 mg/kg p.o. Tmax 1 h
Mice 20 mg/kg p.o. T1/2 1.7 h
体内研究
(In Vivo)

RK-582 (5-20 mg/kg；腹腔注射；按研究方案给药) 在雌性 NOD.CB17-Prkdcscid/J 小鼠的短周期 APC 突变型 COLO-320DM 结直肠癌异种移植模型中呈现剂量依赖性、可耐受的抗肿瘤效力，且已证实具有靶向端锚聚合酶 (tankyrase) 抑制活性[1]。
RK-582 (20 mg/kg; i.p.; 按研究方案给药) 在雌性 BALB/c-nu/nu 小鼠的耐药性长 APC 突变体 HCT-15 结直肠癌异种移植物中未表现出抗肿瘤功效，即便已证实其能靶向抑制端锚聚合酶[1]。
RK-582 (10-20 mg/kg；i.p.；每日 2 次；给药 5 天/停药 2 天，持续 2 周) 经腹腔给药后，在 COLO-320DM 异种移植模型中分别达到 68.8%和 71.1%的肿瘤生长抑制率，且未引发可观察到的毒性[2]。
RK-582 (10-20 mg/kg；经口给药；每日 2 次；给药 5 天/停药 2 天，持续 2 周) 经口服给药后，在 COLO-320DM 异种移植模型中分别实现 52.3%和 52.0%的肿瘤生长抑制率，且未引发可观察到的毒性，同时可调控肿瘤组织中的 Wnt/β-catenin 通路生物标志物[2]。

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.
Clinical Trial
分子量

510.60

Formula

C27H35FN6O3
CAS 号
性状

固体

颜色

White to off-white

运输条件

Room temperature in continental US; may vary elsewhere.
储存方式
Powder -20°C 3 years
4°C 2 years
In solvent -80°C 6 months
-20°C 1 month
溶解性数据
细胞实验： 

DMSO 中的溶解度 : 25 mg/mL (48.96 mM; 超声助溶 (<60°C); 吸湿的 DMSO 对产品的溶解度有显著影响，请使用新开封的 DMSO)

配制储备液
浓度 溶剂体积 质量 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
查看完整储备液配制表

* 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80°C, 6 months; -20°C, 1 month。-80°C储存时，请在6个月内使用，-20°C储存时，请在1个月内使用。

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动物实验：

请根据您的 实验动物和给药方式 选择适当的溶解方案。

以下溶解方案都请先按照 In Vitro 方式配制澄清的储备液，再依次添加助溶剂：
——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用；
以下溶剂前显示的百分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶

  • 方案 一

    请依序添加每种溶剂： 10% DMSO    40% PEG300    5% Tween-80    45% Saline

    Solubility: ≥ 2.5 mg/mL (4.90 mM); 澄清溶液

    此方案可获得 ≥ 2.5 mg/mL（饱和度未知）的澄清溶液。

    以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；再向上述体系中加入 50 μL Tween-80，混合均匀；然后再继续加入 450 μL 生理盐水 定容至 1 mL。

    生理盐水的配制：将 0.9 g 氯化钠，溶解于 ddH₂O 并定容至 100 mL，可以得到澄清透明的生理盐水溶液。
  • 方案 二

    请依序添加每种溶剂： 10% DMSO    90% Corn Oil

    Solubility: ≥ 2.5 mg/mL (4.90 mM); 澄清溶液

    此方案可获得 ≥ 2.5 mg/mL（饱和度未知）的澄清溶液，此方案实验周期在半个月以上的动物实验酌情使用。

    以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 900 μL玉米油中，混合均匀。

动物溶解方案计算器
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由于实验过程有损耗，建议您多配一只动物的量
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%
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如果您的动物是免疫缺陷鼠或者体弱鼠，建议 DMSO 中的在最后工作液体系中的占比尽量不超过 2%。
方案所需 助溶剂 包括：DMSO， ，均可在 MCE 网站选购。 ，Tween 80，均可在 MCE 网站选购。
计算结果
工作液所需浓度 : mg/mL
储备液配制方法 : mg 药物溶于 μL  DMSO（母液浓度为 mg/mL）。
您所需的储备液浓度超过该产品的实测溶解度，以下方案仅供参考，如有需要，请与 MCE 中国技术支持联系。
动物实验体内工作液的配制方法 : 取 μL DMSO 储备液，加入 μL 。 μL ，混合均匀至澄清，再加 μL Tween 80，混合均匀至澄清，再加 μL 生理盐水。
连续给药周期超过半月以上，请谨慎选择该方案。
请确保第一步储备液溶解至澄清状态，从左到右依次添加助溶剂。您可采用超声加热 （超声清洗仪，建议频次 20-40 kHz），涡旋吹打等方式辅助溶解。
纯度 & 产品资料
参考文献

RK-582 相关分类

完整储备液配制表

* 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80°C, 6 months; -20°C, 1 month。-80°C储存时，请在6个月内使用，-20°C储存时，请在1个月内使用。

可选溶剂 浓度 溶剂体积 质量 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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