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Ko 143

Catalog No.GC12711

Inhibitor of the multidrug transporter BCRP

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Ko 143 Chemical Structure

Cas No.: 461054-93-3

Size Price Stock Qty
10mM (in 1mL DMSO)
$91.00
In stock
1mg
$56.00
In stock
5mg
$85.00
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10mg
$137.00
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25mg
$324.00
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50mg
$619.00
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100mg
$1,033.00
In stock

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Sample solution is provided at 25 µL, 10mM.

Product has been cited by 1 publications

Product Documents

Quality Control & SDS

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Protocol

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.

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.

References:

[1]. Weidner LD, et al. The Inhibitor Ko143 Is Not Specific for ABCG2. J Pharmacol Exp Ther. 2015 Sep;354(3):384-93.
[2]. JD Allen 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.
[3]. Wen JH, et al. Effect of Ursolic Acid on Breast Cancer Resistance Protein-mediated Transport of ZD 4522 In Vivo and Vitro. Chin Med Sci J. 2015 Dec;30(4):218-25.
[4]. Hou J, et al. Quantitative determination and pharmacokinetic study of the novel anti-Parkinson's disease candidate drug FLZ in rat brain by high performance liquid chromatography-tandem mass spectrometry. J Pharm Biomed Anal. 2012 Jul;66:232-9.
[5]. Liu K, et al. Metabolism of KO143, an ABCG2 inhibitor. Drug Metab Pharmacokinet. 2017 Aug;32(4):193-200.

Background

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.

Chemical Properties

Cas No. 461054-93-3 SDF
Chemical Name 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
Formula C26H35N3O5 M.Wt 469.59
Solubility 30mg/mL in ethanol; 20mg/mL in DMSO; 25mg/mL in DMF Storage Store at -20°C
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

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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
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Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

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