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]。