V-9302 hydrochloride

V-9302 hydrochloride is a competitive small molecule antagonist of transmembrane glutamine flux that selectively and effectively targets the amino acid transporter ASCT2 (SLC1A5). Pharmacological blockade of ASCT2 with V-9302 leads to reduced cancer cell growth and proliferation, enhanced cell death, and elevated oxidative stress. These effects collectively contribute to potent antitumor responses observed both in vitro and in vivo^[1-3].

V-9302 hydrochloride (10 μM; 24 hours) decreases mitochondrial respiration in VSMCs stimulated with either FBS or PDGF. This suggests that pharmacological inhibition of glutamine transport using V-9302 hydrochloride hinders mitochondrial respiration in growth factor-stimulated and proliferating VSMCs^[4]. Treatment of NCI-Meso-17 cells with V-9302 hydrochloride (5-15 μM) decreases cell growth, impairs spheroid formation, and reduces cell invasion^[5].

V-9302 hydrochloride (75 mg/kg, administered intraperitoneally daily for 21 days) demonstrates potent inhibition of tumor growth in xenograft models of HCT-116 and HT29^[1]. V-9302(12.5 mg/kg/day; i.p; 5 days per week for 3 weeks) markedly suppresses neointima formation in mice^[4]. The combination of CB-839 and V-9302(30 mg/kg, i.p; 15 or 20days) results in glutathione depletion and induces lethal levels of reactive oxygen species (ROS) in GD liver cancer cells. Furthermore, this combination therapy inhibits xenograft growth and promotes apoptosis in vivo^[6]. V-9302 hydrochloride (50 mg/kg; i.p.; daily for 5 days) displays markedly reduced tumor growth in mice^[7]. Pharmacological inhibition of SLC1A5 by V-9302 hydrochloridealtered fibroblast transcriptional profiles from a profibrotic to a fibrosis-resolving state, resulting in reduced fibrosis in a mouse model of lung fibrosis induced by bleomycin treatment^[8].

References:
[1]. Schulte ML, Fu A, et,al. Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med. 2018 Feb;24(2):194-202. doi: 10.1038/nm.4464. Epub 2018 Jan 15. PMID: 29334372; PMCID: PMC5803339.
[2]. Schulte ML, Khodadadi AB, et,al. 2-Amino-4-bis(aryloxybenzyl)aminobutanoic acids: A novel scaffold for inhibition of ASCT2-mediated glutamine transport. Bioorg Med Chem Lett. 2016 Feb 1;26(3):1044-1047. doi: 10.1016/j.bmcl.2015.12.031. Epub 2015 Dec 11. PMID: 26750251; PMCID: PMC4727990.
[3]. Canul-Tec JC, Assal R, et,al. Structure and allosteric inhibition of excitatory amino acid transporter 1. Nature. 2017 Apr 27;544(7651):446-451. doi: 10.1038/nature22064. Epub 2017 Apr 19. PMID: 28424515; PMCID: PMC5410168.
[4]. Park HY, Kim MJ, et,al.V-9302 inhibits proliferation and migration of VSMCs, and reduces neointima formation in mice after carotid artery ligation. Biochem Biophys Res Commun. 2021 Jun 30;560:45-51. doi: 10.1016/j.bbrc.2021.04.079. Epub 2021 May 6. PMID: 33965788.
[5].Adhikary G, Shrestha S, et,al.Mesothelioma cancer cells are glutamine addicted and glutamine restriction reduces YAP1 signaling to attenuate tumor formation. Mol Carcinog. 2023 Apr;62(4):438-449. doi: 10.1002/mc.23497. Epub 2022 Dec 23. PMID: 36562471; PMCID: PMC10071591.
[6]. Jin H, Wang S, et,al. A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer. Elife. 2020 Oct 5;9:e56749. doi: 10.7554/eLife.56749. PMID: 33016874; PMCID: PMC7535927.
[7]. Edwards DN, Ngwa VM, et,al. Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer. J Clin Invest. 2021 Feb 15;131(4):e140100. doi: 10.1172/JCI140100. PMID: 33320840; PMCID: PMC7880417.
[8]. Choudhury M, Schaefbauer KJ, et,al.Targeting Pulmonary Fibrosis by SLC1A5-Dependent Glutamine Transport Blockade. Am J Respir Cell Mol Biol. 2023 Oct;69(4):441-455. doi: 10.1165/rcmb.2022-0339OC. PMID: 37459644; PMCID: PMC10557918.

V-9302 hydrochloride是一种跨膜谷氨酰胺通量的竞争性小分子拮抗剂，选择性有效地靶向氨基酸转运蛋白ASCT2 (SLC1A5)。用V-9302药物阻断ASCT2可导致癌细胞生长和增殖减少、细胞死亡增加和氧化应激升高。这些作用共同促成了体外和体内观察到的有效抗肿瘤反应^[1-3]。

V-9302 hydrochloride (10 μM; 24 hours) 在FBS或PDGF刺激的VSMCs中降低线粒体呼吸。这表明使用V-9302对谷氨酰胺运输的药理学抑制会阻碍生长因子刺激的VSMCs的线粒体呼吸[4]。V-9302 hydrochloride (5-15 μM)处理NCI-Meso-17细胞可抑制细胞生长，减少细胞侵袭^[5]。

V-9302 hydrochloride (75 mg/kg, administered intraperitoneally daily for 21 days)在HCT-116和HT29异种移植模型中显示出对肿瘤生长的有效抑制^[1]。V-9302 hydrochloride (12.5 mg/kg/day; i.p; 5 days per week for 3 weeks) 明显抑制小鼠新生内膜的形成^[4]。CB-839和V-9302 hydrochloride (30 mg/kg, i.p; 15 or 20days) 联合使用可导致GD肝癌细胞中谷胱甘肽耗竭并诱导致死水平的活性氧(ROS)。此外，这种联合疗法在体内抑制异种移植物生长并促进细胞凋亡^[6]。V-9302 hydrochloride (50 mg/kg; i.p.; daily for 5 days) 在小鼠中表现出明显的肿瘤抑制作用^[7]。V-9302 hydrochloride对SLC1A5的药理抑制改变了成纤维细胞的转录谱，使其从纤维化状态转变为纤维化消退状态，导致博来霉素诱导的肺纤维化小鼠模型中的纤维化减少^[8]。