Ko 143
(Synonyms: (3S,6S,12aS)-1,2,3,4,6,7,12,12a-八氢-9-甲氧基-6-(2-甲基丙基)-1,4-二氧代吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-3-丙酸叔丁酯,Ko-143;Ko143) 目录号 : GC12711
Inhibitor of the multidrug transporter BCRP
Cas No.:461054-93-3
Sample solution is provided at 25 µL, 10mM.
Ko 143 is a potent and selective breast cancer resistance protein multidrug transporter (BCRP) inhibitor with IC50 value of 26 nM [1].
BCRP is a member of ATP- binding cassette transport protein superfamily, which is a plasma membrane protein associated with multidrug resistance of cancer cells.It is found in the intestinal epithelium, liver canaliculi, the placental trophoblasts, mammary ducts and lobules, and endothelial cells of veins and capillaries. MDR is the principal reason for the failure of anticancer chemotherapy, where BCRP may act as a broad specificity drug efflux pump and confer multidrug resistance. When overexpressed, BCRP is able to confer the resistance of various cancer cell lines to drugs including topotecan, doxorubicin, daunorubicin and mitoxantrone.
BCRP is the first potent and specific BCRP inhibitor applicable in vivo. When a library of potent compounds was screened in mouse T6400 and human T8 cancer cell line, Ko 143 was identified as the inhibitor with the high inhibitory activity and low cytotoxicity. Additionally, Ko 143 was observed to have 200-fold selectivity over P-glycoprotein and multidrug resistance protein-1 [2]. The effect of Ko 143 in reversing Bcrp-1/BCRP-mediated drug resistance was also observed in mouse T6400 and human T8 cell line respectively. At EC90 concentration of Ko 143, it reversed the Bcrp-1/BCRP-mediated drug resistance in the drug selected T6400 and T8 cell line, resulting in 10-fold sensitization to topotecan and mitoxantrone [2].
In mouse model, oral administration of Ko 143 50 mg/day or higher showed no evidence of acute of delayed cellular toxicity [2]. In Mdr1a/1b-/- mice, oral administration of Ko 143 of 10 mg/kg resulted in increasing plasma topotecan level by 4-6 folds at 30 min and 60 min after oral administration of the drug. It suggested Ko 143 suppressed the multidrug resistance conferred by BCRP [2].
References:
[1] Loevezijn AV et al. , Inhibition of BCRP-mediated drug efflux by fumitremorgin-type indolyl diketopiperazines. Bioorg. Med. Chem. Lett. 2001, 11(1), 29-32.
[2] Allen J D et al. , Potent and Specific Inhibition of the Breast Cancer Resistance Protein Multidrug Transporter in Vitro and in Mouse Intestine by a Novel Analogue of Fumitremorgin C. Mol. Cancer Ther. 2002, 1, 417-425.
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Cell experiment: |
cells are plated at 400 or 1000/well in 96-well plates the night before addition of drugs. A concentration series of drug is applied along one plate axis and left for the duration of the assay. Plates are harvested after 4-5 days while untreated wells are still subconfluent. Relative cell proliferation is quantified with CyQuant or Sybr Green I fluorescent nucleic acid stains. Assays with human cell lines are performed in the presence of 0.1 μm PSC833 to inhibit confounding P-gp activity. |
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Animal experiment: |
Oral toxicity of FTC analogues in mice is tested by mixing 50 mg/mL stocks in DMSO 1:1 with Tween 80 (polyoxyethylene sorbitan mono-oleate) and diluting with 5% w/v glucose such that the final volume administered by oral gavage is 10 μL/g of body weight. Pairs of mice are administered oral doses of 50 mg/kg Ko132, Ko134, Ko143, or vehicle under light methoxyflurane anesthesia. Final tests of 50 mg/kg Ko134 or Ko143 are performed on additional pairs of unanesthetized animals to observe any behavioral effects. Further, another pair of mice receive the higher dose of 100 mg/kg Ko134. For i.p. toxicity tests, the FTC analogue stocks in DMSO are dispersed in at least 10 volumes of sterile corn oil such that the injected volume is 5 μL/g of body weight. After pilot tests at lower doses show no adverse effects, mice (4 per group) are administered vehicle or 10 mg/kg i.p. of Ko132, Ko134, or Ko143. The mice are observed continuously during the first hour after administration and then at increasing intervals for 2 weeks, after which they are sacrificed for histological examination of major organs and structures including brain, salivary glands, heart, lungs, liver, adrenal glands, kidneys, urinary tract, spleen, thymus, bone marrow, pancreas, stomach, intestines, cecum, colon, testes, epididymus, skin, head, trunk, and limbs. |
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References: [1]. Weidner LD, et al. The Inhibitor Ko143 Is Not Specific for ABCG2. J Pharmacol Exp Ther. 2015 Sep;354(3):384-93. |
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| Cas No. | 461054-93-3 | SDF | |
| 别名 | (3S,6S,12aS)-1,2,3,4,6,7,12,12a-八氢-9-甲氧基-6-(2-甲基丙基)-1,4-二氧代吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-3-丙酸叔丁酯,Ko-143;Ko143 | ||
| 化学名 | tert-butyl 3-((3R,6S,12aR)-6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indol-3-yl)propanoate | ||
| Canonical SMILES | O=C1N2[C@@H](CC(C)C)C(NC3=C4C=CC(OC)=C3)=C4C[C@@H]2C(N[C@@H]1CCC(OC(C)(C)C)=O)=O | ||
| 分子式 | C26H35N3O5 | 分子量 | 469.59 |
| 溶解度 | 30mg/mL in ethanol; 20mg/mL in DMSO; 25mg/mL in DMF | 储存条件 | Store at -20°C |
| General tips | 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 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1295 mL | 10.6476 mL | 21.2952 mL |
| 5 mM | 0.4259 mL | 2.1295 mL | 4.259 mL |
| 10 mM | 0.213 mL | 1.0648 mL | 2.1295 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
