V-9302
目录号 : GC34852
An inhibitor of ASCT2
Cas No.:1855871-76-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
HCC1806 cells |
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Preparation Method |
Cells were plated in 96-well plates for 24 h before the assay. Cells were treated with either vehicle or the indicated concentrations（25 μM） of V-9302 hydrochloride for 48 h |
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Reaction Conditions |
25 μM，48h |
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Applications |
Silencing of ASCT2 and V-9302 hydrochloride exposure in HCC1806 cells resulted in analogous downstream effects, including markedly decreased phosphorylated (p)-S6 levels and a modest decrease in p-ERK levels. |
| Animal experiment [2]: | |
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Animal models |
6-week-old female athymic nude mice |
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Preparation Method |
Chronic-exposure studies in tumor-bearing mice. Athymic nude mice (Hsd:Athymic nude-Foxn1nu) bearing HCT-116 (KRAS-G13D) or HT29 (BRAF-V600E) cell line xenografts were treated with 75 mg V-9302 hydrochloride per kg body weight per day for 21 d. |
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Dosage form |
75 mg V-9302 hydrochloride per kg body weight per day for 21 day |
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Applications |
V-9302 hydrochloride led to significantly decreased expression of p-S6 in tumor tissue in both HCT-116 and HT29 xenografts. In addition to decreased p-S6 IHC staining, V-9302 treatment led to elevated levels of cleaved caspase 3 in both HCT-116 and HT29 xenografts. |
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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. |
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V-9302 is an inhibitor of amino acid transporter 2 (ASCT2).1 It inhibits glutamine uptake with IC50 values of 9 and 9.6 ?M for the rat and human transporters, respectively. V-9302 also inhibits glutamine uptake in HEK293 cells and reduces cell viability of a variety of cancer cell lines, including HCT116, HT-29, COLO 205, and RKO cells (EC50s = 8.9, 9.4, 14.5, and 8.3 ?M, respectively).2 It reduces glutamine uptake into tumor tissue and prevents tumor growth in HCT116 and HT-29 mouse xenograft models expressing K-RasG13D and BRAFV600E mutations, respectively, when administered at a dose of 75 mg/kg per day for 21 days.
1.Schulte, M.L., Khodadadi, A.B., Cuthbertson, M.L., et al.2-Amino-4-bis(aryloxybenzyl)aminobutanoic acids: A novel scaffold for inhibition of ASCT2-mediated glutamine transportBioorg. Med. Chem. Lett.26(3)1044-1047(2016) 2.Schulte, M.L., Fu, A., Zhao, P., et al.Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical modelsNat. Med.24(2)194-202(2018)
| Cas No. | 1855871-76-9 | SDF | |
| Canonical SMILES | O=C(O)[C@@H](N)CCN(CC1=CC=CC=C1OCC2=CC=CC(C)=C2)CC3=CC=CC=C3OCC4=CC=CC(C)=C4 | ||
| 分子式 | C34H38N2O4 | 分子量 | 538.68 |
| 溶解度 | DMSO : 125 mg/mL (232.05 mM);Water : < 0.1 mg/mL (insoluble) | 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 | 1.8564 mL | 9.2819 mL | 18.5639 mL |
| 5 mM | 0.3713 mL | 1.8564 mL | 3.7128 mL |
| 10 mM | 0.1856 mL | 0.9282 mL | 1.8564 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。
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.PMID:33965788DOI:10.1016/j.bbrc.2021.04.079.
Rapidly proliferating cells such as vascular smooth muscle cells (VSMCs) require metabolic programs to support increased energy and biomass production. Thus, targeting glutamine metabolism by inhibiting glutamine transport could be a promising strategy for vascular disorders such as atherosclerosis, stenosis, and restenosis. V-9302, a competitive antagonist targeting the glutamine transporter, has been investigated in the context of cancer; however, its role in VSMCs is unclear. Here, we examined the effects of blocking glutamine transport in fetal bovine serum (FBS)- or platelet-derived growth factor (PDGF)-stimulated VSMCs using V-9302. We found that V-9302 inhibited mTORC1 activity and mitochondrial respiration, thereby suppressing FBS- or PDGF-stimulated proliferation and migration of VSMCs. Moreover, V-9302 attenuated carotid artery ligation-induced neointima in mice. Collectively, the data suggest that targeting glutamine transport using V-9302 is a promising therapeutic strategy to ameliorate occlusive vascular disease.
Neddylation inhibition induces glutamine uptake and metabolism by targeting CRL3SPOP E3 ligase in cancer cells
Nat Commun 2022 May 31;13(1):3034.PMID:35641493DOI:10.1038/s41467-022-30559-2.
Abnormal neddylation activation is frequently observed in human cancers and neddylation inhibition has been proposed as a therapy for cancer. Here, we report that MLN4924, a small-molecule inhibitor of neddylation activating enzyme, increases glutamine uptake in breast cancer cells by causing accumulation of glutamine transporter ASCT2/SLC1A5, via inactivation of CRL3-SPOP E3 ligase. We show the E3 ligase SPOP promotes ASCT2 ubiquitylation, whereas SPOP itself is auto-ubiquitylated upon glutamine deprivation. Thus, SPOP and ASCT2 inversely regulate glutamine uptake and metabolism. SPOP knockdown increases ASCT2 levels to promote growth which is rescued by ASCT2 knockdown. Adding ASCT2 inhibitor V-9302 enhances MLN4924 suppression of tumor growth. In human breast cancer specimens, SPOP and ASCT2 levels are inversely correlated, whereas lower SPOP with higher ASCT2 predicts a worse patient survival. Collectively, our study links neddylation to glutamine metabolism via the SPOP-ASCT2 axis and provides a rational drug combination for enhanced cancer therapy.
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.PMID:33320840DOI:10.1172/JCI140100.
Rapidly proliferating tumor and immune cells need metabolic programs that support energy and biomass production. The amino acid glutamine is consumed by effector T cells and glutamine-addicted triple-negative breast cancer (TNBC) cells, suggesting that a metabolic competition for glutamine may exist within the tumor microenvironment, potentially serving as a therapeutic intervention strategy. Here, we report that there is an inverse correlation between glutamine metabolic genes and markers of T cell-mediated cytotoxicity in human basal-like breast cancer (BLBC) patient data sets, with increased glutamine metabolism and decreased T cell cytotoxicity associated with poor survival. We found that tumor cell-specific loss of glutaminase (GLS), a key enzyme for glutamine metabolism, improved antitumor T cell activation in both a spontaneous mouse TNBC model and orthotopic grafts. The glutamine transporter inhibitor V-9302 selectively blocked glutamine uptake by TNBC cells but not CD8+ T cells, driving synthesis of glutathione, a major cellular antioxidant, to improve CD8+ T cell effector function. We propose a "glutamine steal" scenario, in which cancer cells deprive tumor-infiltrating lymphocytes of needed glutamine, thus impairing antitumor immune responses. Therefore, tumor-selective targeting of glutamine metabolism may be a promising therapeutic strategy in TNBC.
Inhibition of alanine-serine-cysteine transporter 2-mediated auto-enhanced photodynamic cancer therapy of co-nanoassembly between V-9302 and photosensitizer
J Colloid Interface Sci 2022 May 27;629(Pt B):773-784.PMID:36195017DOI:10.1016/j.jcis.2022.05.044.
The efficiency of reactive oxygen species (ROS)-based photodynamic therapy (PDT) is far from satisfactory, because cancer cells can adapt to PDT by upregulating glutathione (GSH) levels. The GSH levels in tumor cells are determined based on glutamine availability via alanine-serine-cysteine transporter 2 (ASCT2)-mediated entry into cells. Herein, we develop co-assembled nanoparticles (PPa/V-9302 NPs) of the photosensitizer pyropheophorbide a (PPa) and V-9302 (a known inhibitor of ASCT2) in a 1:1 M ratio using a one-step precipitation method to auto-enhance photodynamic therapy. The computational simulations revealed that PPa and V-9302 could self-assemble through different driving forces, such as π-π stacking, hydrophobic interactions, and ionic bonds. Such PPa/V-9302 NPs could disrupt the intracellular redox homeostasis due to enhanced ROS production via PPa-induced PDT and reduced GSH synthesis via inhibition of the ASCT2-mediated glutamine flux by V-9302. The in vivo assays reveal that PPa/V-9302 NPs could increase the drug accumulation in tumor sites and suppress tumor growth in BALB/c mice bearing mouse breast carcinoma (4 T1) tumor. Our findings provide a new paradigm for the rational design of the PDT-based combinational cancer therapy.
A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer
Elife 2020 Oct 5;9:e56749.PMID:33016874DOI:10.7554/eLife.56749.
The dependency of cancer cells on glutamine may be exploited therapeutically as a new strategy for treating cancers that lack druggable driver genes. Here we found that human liver cancer was dependent on extracellular glutamine. However, targeting glutamine addiction using the glutaminase inhibitor CB-839 as monotherapy had a very limited anticancer effect, even against the most glutamine addicted human liver cancer cells. Using a chemical library, we identified V-9302, a novel inhibitor of glutamine transporter ASCT2, as sensitizing glutamine dependent (GD) cells to CB-839 treatment. Mechanically, a combination of CB-839 and V-9302 depleted glutathione and induced reactive oxygen species (ROS), resulting in apoptosis of GD cells. Moreover, this combination also showed tumor inhibition in HCC xenograft mouse models in vivo. Our findings indicate that dual inhibition of glutamine metabolism by targeting both glutaminase and glutamine transporter ASCT2 represents a potential novel treatment strategy for glutamine addicted liver cancers.