LW6 (HIF-1α inhibitor)
(Synonyms: HIF-1α inhibitor; LW8) 目录号 : GC32724
LW6是一种缺氧诱导因子1(hypoxia inducing factor 1, HIF)抑制剂,通过降解HIF-1α有效抑制HIF-1α的积累,但不影响缺氧时HIF- 1a mRNA水平。
Cas No.:934593-90-5
Sample solution is provided at 25 µL, 10mM.
LW6 is a hypoxia-inducing factor 1(HIF) inhibitor, which effectively inhibits HIF-1α accumulation by degrading HIF-1α, but does not affect HIF-1A mRNA level during hypoxia. LW6 inhibits the expression of HIF and MDH2, with IC50 values of 4.4 and 6.3µM, respectively [1-2].
LW6(0.01-25µM ; 30 min) enhanced significantly the cellular accumulation of mitoxantrone(BCRP substrate)in MDCKII-BCRP cells (overexpressed BCRP)[3]. LW6 inhibited hypoxia-induced HIF1α expression at 20 mM in A549 cells, and at this concentration,LW6 induced hypoxia-selective apoptosis and decreased mitochondrial membrane potential[4]. LW6(40-160µM) inhibited proliferation and induced cell death in a dose-dependent manner In 6606PDA and MIA PaCa-2 cells[5]. LW6 (80µM)significantly inhibited migration,besides,LW6 reduced cell proliferation and induced cell death in a dose dependent manner[6]. LW6(30 µµ; 72 h) stimulates T cells to decrease HIF-1α levels[7]. LW6 inhibited T-cell clonal expansion in two-way mixed lymphocyte reaction (MLR) [8].
LW6(5 mg/kg;i.v/p.o) exhibited a small volume of distribution and a short terminal half-life. LW6 was slowly degraded in mouse liver microsomes and serum. About 54% or 44.8% of LW6 was available systemically as APA in the mouse after a single intravenous or oral administration, respectively[1].
References:
[1]. Lee K, Lee JH, et,al. (Aryloxyacetylamino)benzoic acid analogues: A new class of hypoxia-inducible factor-1 inhibitors. J Med Chem. 2007 Apr 5;50(7):1675-84. doi: 10.1021/jm0610292. Epub 2007 Mar 1. PMID: 17328532.
[2]. Naik R, Won M, et,al.Synthesis and structure-activity relationship study of chemical probes as hypoxia induced factor-1α/malate dehydrogenase 2 inhibitors. J Med Chem. 2014 Nov 26;57(22):9522-38. doi: 10.1021/jm501241g. Epub 2014 Nov 12. PMID: 25356789.
[3]. Song JG, Lee YS, et,al. Discovery of LW6 as a new potent inhibitor of breast cancer resistance protein. Cancer Chemother Pharmacol. 2016 Oct;78(4):735-44. doi: 10.1007/s00280-016-3127-2. Epub 2016 Aug 12. PMID: 27520631.
[4]. Sato M, Hirose K, et,al.LW6, a hypoxia-inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells. Mol Med Rep. 2015 Sep;12(3):3462-3468. doi: 10.3892/mmr.2015.3862. Epub 2015 May 27. PMID: 26017562; PMCID: PMC4526100.
[5]. Zhang X, Kumstel S, et,al. LW6 enhances chemosensitivity to gemcitabine and inhibits autophagic flux in pancreatic cancer. J Adv Res. 2019 Apr 24;20:9-21. doi: 10.1016/j.jare.2019.04.006. PMID: 31193017; PMCID: PMC6514270.
[6]. Zhang X, Liu P, et,al.Metformin and LW6 impairs pancreatic cancer cells and reduces nuclear localization of YAP1. J Cancer. 2020 Jan 1;11(2):479-487. doi: 10.7150/jca.33029. PMID: 31897243; PMCID: PMC6930432.
[7]. Eleftheriadis T, Pissas G, et,al. Malate dehydrogenase-2 inhibitor LW6 promotes metabolic adaptations and reduces proliferation and apoptosis in activated human T-cells. Exp Ther Med. 2015 Nov;10(5):1959-1966. doi: 10.3892/etm.2015.2763. Epub 2015 Sep 22. PMID: 26640580; PMCID: PMC4665222.
[8]. Eleftheriadis T, Pissas G, et,al.Comparison of the effect of the aerobic glycolysis inhibitor dichloroacetate and of the Krebs cycle inhibitor LW6 on cellular and humoral alloimmunity. Biomed Rep. 2017 Nov;7(5):439-444. doi: 10.3892/br.2017.980. Epub 2017 Sep 11. PMID: 29181155; PMCID: PMC5700391.
LW6是一种缺氧诱导因子1(hypoxia inducing factor 1, HIF)抑制剂,通过降解HIF-1α有效抑制HIF-1α的积累,但不影响缺氧时HIF- 1a mRNA水平。LW6抑制HIF和MDH2的表达,IC50值分别为4.4 µM和6.3µM[1-2]。
LW6(0.01 -25µM;30min)显著增强MDCKII-BCRP细胞(过表达BCRP)中米托蒽醌(BCRP底物)的细胞积累[3]。LW6抑制A549细胞缺氧诱导的HIF1α在20 mM处的表达,在此浓度下,LW6诱导缺氧选择性凋亡,降低线粒体膜电位[4]。LW6(40-160µM)在6606PDA和MIA PaCa-2细胞中呈剂量依赖性抑制增殖并诱导细胞死亡[5]。LW6(80µM)显著抑制迁移,并呈剂量依赖性降低细胞增殖和诱导细胞死亡[6]。LW6(30µµ;72 h)刺激T细胞降低HIF-1α水平[7]。LW6抑制双向混合淋巴细胞反应(MLR)中T细胞克隆扩增[8]。
LW6(5 mg/kg;i.v/p.o;0-24h)具有体积分布小、末端半衰期短的特点。LW6在小鼠肝微粒体和血清中缓慢降解。经单次静脉或口服给药后,小鼠体内约54%或44.8%的LW6以APA的形式存在[1]。
| Cell experiment [1]: | |
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Cell lines |
MDCKII-BCRP cells (overexpressing BCRP) |
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Preparation Method |
Cells were seeded into a 96-well plate. At 3 days post-seeding, cells were incubated with mitoxantrone (5µM) with/without inhibitor LW6 over the concentration range of 0.01-25µM. After incubation for 30 min, the drug solution was removed and the cells were washed twice with ice-cold PBS. |
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Reaction Conditions |
0.01-25µM; 30 min |
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Applications |
LW6 enhanced significantly the cellular accumulation of mitoxantrone(BCRP substrate). |
| Animal experiment [2]: | |
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Animal models |
Male ICR mice |
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Preparation Method |
Mice were given a single intravenous (i.v.;5 mg/kg) or oral dose (p.o.;5 mg/kg) of LW6. |
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Dosage form |
5 mg/kg;i.v/p.o; |
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Applications |
LW6 exhibited a small volume of distribution (0.5 ±0.1 L/kg), and a short terminal half-life (0.6±0.1 h). LW6 was slowly degraded in mouse liver microsomes (t1/2 > 1 h) and serum (t1/2 > 6 h). About 54% or 44.8% of LW6 was available systemically as APA in the mouse after a single intravenous or oral administration, respectively. |
|
References: [1]. Song JG, Lee YS, et,al.Discovery of LW6 as a new potent inhibitor of breast cancer resistance protein. Cancer Chemother Pharmacol. 2016 Oct;78(4):735-44. doi: 10.1007/s00280-016-3127-2. Epub 2016 Aug 12. PMID: 27520631. |
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| Cas No. | 934593-90-5 | SDF | |
| 别名 | HIF-1α inhibitor; LW8 | ||
| Canonical SMILES | O=C(OC)C1=CC=C(O)C(NC(COC2=CC=C(C3(C4)CC5CC4CC(C5)C3)C=C2)=O)=C1 | ||
| 分子式 | C26H29NO5 | 分子量 | 435.51 |
| 溶解度 | DMSO : ≥ 33 mg/mL (75.77 mM) | 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 | 2.2962 mL | 11.4808 mL | 22.9616 mL |
| 5 mM | 0.4592 mL | 2.2962 mL | 4.5923 mL |
| 10 mM | 0.2296 mL | 1.1481 mL | 2.2962 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。
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Quality Control & SDS
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