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LW6 (HIF-1α inhibitor) Sale

(Synonyms: HIF-1α inhibitor; LW8) 目录号 : GC32724

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 (HIF-1α inhibitor) Chemical Structure

Cas No.:934593-90-5

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10mM (in 1mL DMSO)
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5mg
¥462.00
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10mg
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25mg
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50mg
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100mg
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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Cell experiment [1]:

Cell lines

MDCKII-BCRP cells (overexpressing BCRP)

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.

Reaction Conditions

0.01-25µM; 30 min

Applications

LW6 enhanced significantly the cellular accumulation of mitoxantrone(BCRP substrate).

Animal experiment [2]:

Animal models

Male ICR mice

Preparation Method

Mice were given a single intravenous (i.v.;5 mg/kg) or oral dose (p.o.;5 mg/kg) of LW6.

Dosage form

5 mg/kg;i.v/p.o;

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.
[2].Lee JY, Lee K, et,al.Pharmacokinetic Characterization of LW6, a Novel Hypoxia-Inducible Factor-1α (HIF-1α) Inhibitor in Mice. Molecules. 2021 Apr 12;26(8):2226. doi: 10.3390/molecules26082226. PMID: 33921487; PMCID: PMC8070284.

产品描述

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].

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]。

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.

Chemical Properties

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
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1 mM 2.2962 mL 11.4808 mL 22.9616 mL
5 mM 0.4592 mL 2.2962 mL 4.5923 mL
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Research Update

The hypoxia-inducible factor 1 inhibitor LW6 mediates the HIF-1α/PD-L1 axis and suppresses tumor growth of hepatocellular carcinoma in vitro and in vivo

Eur J Pharmacol 2022 Sep 5;930:175154.PMID:35868447DOI:10.1016/j.ejphar.2022.175154.

The low survival rate of hepatocellular carcinoma (HCC) remains a major challenge for clinicians and patients, and its progression may be related to hypoxia-inducible factor (HIF) and PD-L1. LW6 is a drug that inhibits hypoxia by reducing HIF-1α accumulation and gene transcriptional activity. However, its effect and regulatory mechanism in HCC remain to be revealed, especially under hypoxic conditions. The HIF-1α and PD-L1 expression in HCC specimens and paracarcinoma tissues was evaluated by a tissue microarray (TMA). The effects of LW6 were evaluated by cell viability, colony formation, and Transwell assays and xenografted nude mice. Cell cycle and apoptosis of HCC cells were detected by flow cytometry. The effects of LW6 on HIF-1α signaling and its targets PD-L1 and VEGF were evaluated through qRT-PCR, Western blots, Cell transfection, Transwell migration and invasion assays, immunohistochemistry, immunofluorescence and luciferase assays. In this study, we found that LW6 had antiproliferative effects on HCC and promoted HCC cell apoptosis, inhibited their migration and invasion, and affected their cell cycle. LW6 dramatically decreased HIF-1α expression through the VHL-dependent proteasome system pathway, inhibited HIF-1α transcriptional activation, and reduced PD-L1 expression by inhibiting EGFR pathway activation. These results suggest that LW6 can promote apoptosis of HCC cells by inhibiting HIF-1α, inhibit tumor angiogenesis, and downregulate the expression of PD-L1, which is an effective choice for the treatment of HCC. Moreover, inhibiting the hypoxic microenvironment combined with immunotherapy is expected to be a potentially effective strategy.

LW6, a novel HIF-1 inhibitor, promotes proteasomal degradation of HIF-1alpha via upregulation of VHL in a colon cancer cell line

Biochem Pharmacol 2010 Oct 1;80(7):982-9.PMID:20599784DOI:10.1016/j.bcp.2010.06.018.

Hypoxia-inducible factor HIF-1 is responsible for radiation resistance and poor prognosis in cancer therapy. As part of our drug discovery program, a novel HIF inhibitor, LW6, was identified as a small compound that inhibits the accumulation of HIF-1alpha. We found that LW6 decreased HIF-1alpha protein expression without affecting HIF-1beta expression. MG132, a proteasome inhibitor, protected HIF-1alpha from LW6-induced proteasomal degradation, indicating that LW6 affects the stability of the HIF-1alpha protein. We found that LW6 promoted the degradation of wild type HIF-1alpha, but not of a DM-HIF-1alpha with modifications of P402A and P564A, at hydroxylation sites in the oxygen-dependent degradation domain (ODDD). LW6 did not affect the activity of prolyl hydroxylase (PHD), but induced the expression of von Hippel-Lindau (VHL), which interacts with prolyl-hydroxylated HIF-1alpha for proteasomal degradation. In the presence of LW6, knockdown of VHL did not abolish HIF-1alpha protein accumulation, indicating that LW6 degraded HIF-1alpha via regulation of VHL expression. In mice carrying xenografts of human colon cancer HCT116 cells, LW6 demonstrated strong anti-tumor efficacy in vivo and caused a decrease in HIF-1alpha expression in frozen-tissue immunohistochemical staining. These data suggest that LW6 may be valuable in the development of a HIF-1alpha inhibitor for cancer treatment.

HIF-1α suppressing small molecule, LW6, inhibits cancer cell growth by binding to calcineurin b homologous protein 1

Biochem Biophys Res Commun 2015 Feb 27;458(1):14-20.PMID:25603055DOI:10.1016/j.bbrc.2015.01.031.

Hypoxia inducible factor-1 alpha (HIF-1α) plays an important role in angiogenesis and metastasis and is a promising therapeutic target for the development of anti-cancer drugs. We recently developed a new synthetic small molecule inhibitor of HIF-1α, LW6, which results in inhibition of angiogenesis. To investigate its underlying mechanism, target protein identification was conducted by reverse chemical proteomics using phage display. We identified calcineurin b homologous protein 1 (CHP1) as a target protein of LW6, which specifically binds to CHP1 in a Ca(2+) dependent manner. Covalent labeling of LW6 using photoaffinity and click chemistry demonstrated its co-localization with CHP1 in live cells. HIF-1α was decreased by CHP1 knockdown in HepG2 cells, and angiogenesis was not induced in HUVEC cells by treatment with conditioned media from CHP1 knockdown cells compared to the control. These data demonstrated that LW6 inhibited HIF-1α stability via direct binding with CHP1 resulting in suppression of angiogenesis, providing a new insight into the role of CHP1 in HIF-1α regulation. LW6 could serve as a new chemical probe to explore CHP1 function.

Chemical biology approach for the development of hypoxia inducible factor (HIF) inhibitor LW6 as a potential anticancer agent

Arch Pharm Res 2015 Sep;38(9):1563-74.PMID:26310207DOI:10.1007/s12272-015-0632-5.

Intratumoral hypoxia has long been considered to be a driving force in tumor progression as well as a negative prognostic factor in human cancers. The discovery of hypoxia inducible factors (HIFs), which mediate transcriptional responses to changes in oxygen levels, has renewed enthusiasm for drug discovery and the development of targeted therapies in this field. LW6 represents an important new class of small molecules that inhibit HIF-1; it has been major source for diverse lead compounds including HIF-1α inhibitors. Through a chemical biology approach, LW6-derived chemical probes were successfully utilized for the identification of the direct targeting of a protein in cancer. LW6 provides a valuable platform for the discovery and development of small molecule inhibitors of HIF-1α-dependent tumor progression, metabolic reprogramming, and angiogenesis.

Pharmacokinetic Characterization of LW6, a Novel Hypoxia-Inducible Factor-1α (HIF-1α) Inhibitor in Mice

Molecules 2021 Apr 12;26(8):2226.PMID:33921487DOI:10.3390/molecules26082226.

LW6, an (aryloxyacetylamino)benzoic acid derivative, was recently identified to be an inhibitor of hypoxia-inducible factor-1α (HIF-1α), which is an attractive target for cancer therapeutics. Although LW6 is known to act by inhibiting the accumulation of HIF-1α, pharmacokinetics needs to be evaluated to assess its potential as an anti-tumor agent. Here, we investigated the plasma pharmacokinetics and metabolism of LW6 in mice. LW6 exhibited a small volume of distribution (0.5 ± 0.1 L/kg), and a short terminal half-life (0.6 ± 0.1 h). Following intravenous or oral administration, LW6 was rapidly converted to its active metabolite, (4-adamantan-1-yl-phenoxy)acetic acid (APA). Although LW6 was rapidly absorbed, its oral bioavailability, estimated using AUClast values, was low (1.7 ± 1.8%). It 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. Thus, our results indicated the need to simultaneously consider the active metabolite as well as the parent compound for successful evaluation during lead optimization.