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
Ko 143是一种有效的选择性乳腺癌耐药蛋白（BCRP; ABCG2）抑制剂，IC50值为23nM。
Cas No.:461054-93-3
Sample solution is provided at 25 µL, 10mM.
Ko 143 is a potent and selective inhibitor of breast cancer resistance protein (BCRP; ABCG2) with an IC50 value of 23nM[1]. BCRP is an important transmembrane efflux transporter in the body and belongs to the ATP-binding cassette transporter superfamily. It is mainly responsible for the excretion of endogenous and exogenous substances into the extracellular space[2]. The selectivity of Ko 143 is more than 200 times that of P-glycoprotein (P-gp) and multidrug resistance protein-1 (MRP-1)[3].
In vitro, Ko 143 (1.5µM) treatment of U251-V cells expressing ABCG2 for 4h inhibited ABCG2 and restored the intracellular accumulation of the photosensitizer dihydrochlorin e6 (Ce6)[4]. Ko 143 (1μM) treatment of MCF7 cells significantly increased the intracellular fluorescence of mitoxantrone[5]. Treatment of HeLa1A1 cells expressing UGT1A1 with Ko 143 (5, 20μM) significantly reduced the cellular excretion of DMC-O-glucuronide[6].
In vivo, oral treatment of Mdr1a/1b-/- mice with Ko 143 (10mg/kg) increased the oral availability of topotecan and increased its plasma concentration by 4-6 fold at 30 and 60min after administration[7].
References:
[1] Yu Q, Dehghani-Ghahnaviyeh S, Rasouli A, et al. Modulation of ABCG2 Transporter Activity by Ko143 Derivatives[J]. ACS Chemical Biology, 2024, 19(11): 2304-2313.
[2] Choudhuri S, Klaassen C D. Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters[J]. International journal of toxicology, 2006, 25(4): 231-259.
[3] Lustig S D, Kodali S K, Longo S L, et al. Ko143 reverses MDR in glioblastoma via deactivating P-glycoprotein, sensitizing a resistant phenotype to TMZ treatment[J]. Anticancer Research, 2022, 42(2): 723-730.
[4] Gaber S A A, Müller P, Zimmermann W, et al. ABCG2-mediated suppression of chlorin e6 accumulation and photodynamic therapy efficiency in glioblastoma cell lines can be reversed by KO143[J]. Journal of Photochemistry and Photobiology B: Biology, 2018, 178: 182-191.
[5] Wang J S, Zhu H J, Markowitz J S, et al. Antipsychotic drugs inhibit the function of breast cancer resistance protein[J]. Basic & clinical pharmacology & toxicology, 2008, 103(4): 336-341.
[6] Zhang B, Yang J, Qin Z, et al. Mechanism of the efflux transport of demethoxycurcumin-O-glucuronides in HeLa cells stably transfected with UDP-glucuronosyltransferase 1A1[J]. Plos one, 2019, 14(5): e0217695.
[7] Allen J D, Van Loevezijn A, Lakhai J M, 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[J]. Molecular cancer therapeutics, 2002, 1(6): 417-425.
Ko 143是一种有效的选择性乳腺癌耐药蛋白（BCRP; ABCG2）抑制剂，IC50值为23nM[1]。BCRP是体内重要的跨膜外排转运体，属于ATP结合盒转运体超家族，主要负责将内、外源性物质排至细胞外[2]。Ko 143的选择性是P-糖蛋白（P-gp）和多药耐药蛋白-1（MRP-1 ）的200倍以上[3]。
在体外，Ko 143（1.5µM）处理表达 ABCG2的U251-V细胞4h，抑制了ABCG2，恢复了光敏剂二氢卟酚e6（Ce6）在细胞内的积累[4]。Ko 143（1μM）处理MCF7细胞，显著增加了米托蒽醌（mitoxantrone）的细胞内荧光[5]。Ko 143（5、20μM）处理表达UGT1A1的HeLa1A1细胞，显著减少了DMC-O-葡萄糖醛酸苷的细胞排泄[6]。
在体内，Ko 143（10mg/kg）通过口服治疗Mdr1a/1b-/-小鼠，给药后30min和 60min，增加了拓扑替康（topotecan）的口服可用性，使其在血浆的浓度升高了4-6倍[7]。
| Cell experiment [1]: | |
Cell lines | U251-V cells、U251-EV cells |
Preparation Method | Cells were plated at a density of 1x104 per well in flat bottom 96-well plates in 6 replicates per data point and grown for 6-8h in medium with 10% fetal calf serum (FCS). Sensitization of the cells with 5 or 10µM Chlorin e6 (Ce6) with or without 1.5µM Ko 143 was performed for 4h in 100µL of fresh medium with 2% FCS. The medium was replaced with 100µL of medium without phenol red containing supplements and 2% serum as listed above. At the end of the incubation period, cells were gently washed with pre-warmed PBS and supplied with serum free DMEM medium without phenol red. After irradiation with a series of light doses (0.5-8J/cm2), cells were incubated in 10% FCS-containing DMEM medium for 4h at 37°C in the incubator. For each experiment, a dark control was included in which cells were incubated with Ce6, but not irradiated. |
Reaction Conditions | 1.5µM; 4h |
Applications | Ko 143 significantly reduced the cellular excretion of Ce6. |
References: | |
| 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
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- Purity: >98.00%
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