LOC14
(Synonyms: 2-((4-(环丙烷羰基)哌嗪-1-基)甲基)苯并[D]异噻唑-3(2H)-酮) 目录号 : GC36473
A PDI inhibitor
Cas No.:877963-94-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
LOC14 is an inhibitor of protein disulfide isomerase (PDI; Kd = 62 nM).1 It inhibits PDI chaperone activity in an insulin aggregation assay when used at a concentration of 75 ?M. LOC14 reduces PC12 cell death induced by the misfolded huntingtin protein mHTTQ103 (EC50 = 500 nM). It reduces medium spiny neuron (MSN) degeneration in a rat postnatal cortical brain slice model of mHTTQ73-induced Huntington’s disease.
1.Kaplan, A., Gaschler, M.M., Dunn, D.E., et al.Small molecule-induced oxidation of protein disulfide isomerase is neuroprotectiveProc. Natl. Acad. Sci. USA112(17)E2245-E2252(2015)
| Cas No. | 877963-94-5 | SDF | |
| 别名 | 2-((4-(环丙烷羰基)哌嗪-1-基)甲基)苯并[D]异噻唑-3(2H)-酮 | ||
| Canonical SMILES | O=C(C(C=CC=C1)=C1S2)N2CN3CCN(C(C4CC4)=O)CC3 | ||
| 分子式 | C16H19N3O2S | 分子量 | 317.41 |
| 溶解度 | DMSO: 25 mg/mL (78.76 mM) | 储存条件 | 4°C, protect from light ,unstable in solution, ready to use. |
| 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 | 3.1505 mL | 15.7525 mL | 31.505 mL |
| 5 mM | 0.6301 mL | 3.1505 mL | 6.301 mL |
| 10 mM | 0.315 mL | 1.5752 mL | 3.1505 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。
Inhibition of PDIA3 in club cells attenuates osteopontin production and lung fibrosis
Thorax 2022 Jul;77(7):669-678.PMID:34400514DOI:10.1136/thoraxjnl-2021-216882.
Background: The role of club cells in the pathology of idiopathic pulmonary fibrosis (IPF) is not well understood. Protein disulfide isomerase A3 (PDIA3), an endoplasmic reticulum-based redox chaperone required for the functions of various fibrosis-related proteins; however, the mechanisms of action of PDIA3 in pulmonary fibrosis are not fully elucidated. Objectives: To examine the role of club cells and PDIA3 in the pathology of pulmonary fibrosis and the therapeutic potential of inhibition of PDIA3 in lung fibrosis. Methods: Role of PDIA3 and aberrant club cells in lung fibrosis was studied by analyses of human transcriptome dataset from Lung Genomics Research Consortium, other public resources, the specific deletion or inhibition of PDIA3 in club cells and blocking SPP1 downstream of PDIA3 in mice. Results: PDIA3 and club cell secretory protein (SCGB1A1) signatures are upregulated in IPF compared with control patients. PDIA3 or SCGB1A1 increases also correlate with a decrease in lung function in patients with IPF. The bleomycin (BLM) model of lung fibrosis showed increases in PDIA3 in SCGB1A1 cells in the lung parenchyma. Ablation of Pdia3, specifically in SCGB1A1 cells, decreases parenchymal SCGB1A1 cells along with fibrosis in mice. The administration of a PDI inhibitor LOC14 reversed the BLM-induced parenchymal SCGB1A1 cells and fibrosis in mice. Evaluation of PDIA3 partners revealed that SPP1 is a major interactor in fibrosis. Blocking SPP1 attenuated the development of lung fibrosis in mice. Conclusions: Our study reveals a new relationship with distally localised club cells, PDIA3 and SPP1 in lung fibrosis and inhibition of PDIA3 or SPP1 attenuates lung fibrosis.
The Emerging Landscape of Small-Molecule Therapeutics for the Treatment of Huntington's Disease
J Med Chem 2022 Dec 22;65(24):15993-16032.PMID:36490325DOI:10.1021/acs.jmedchem.2c00799.
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT). The new insights into HD's cellular and molecular pathways have led to the identification of numerous potent small-molecule therapeutics for HD therapy. The field of HD-targeting small-molecule therapeutics is accelerating, and the approval of these therapeutics to combat HD may be expected in the near future. For instance, preclinical candidates such as naphthyridine-azaquinolone, AN1, AN2, CHDI-00484077, PRE084, EVP4593, and LOC14 have shown promise for further optimization to enter into HD clinical trials. This perspective aims to summarize the advent of small-molecule therapeutics at various stages of clinical development for HD therapy, emphasizing their structure and design, therapeutic effects, and specific mechanisms of action. Further, we have highlighted the key drivers involved in HD pathogenesis to provide insights into the basic principle for designing promising anti-HD therapeutic leads.
Small molecule-induced oxidation of protein disulfide isomerase is neuroprotective
Proc Natl Acad Sci U S A 2015 Apr 28;112(17):E2245-52.PMID:25848045DOI:10.1073/pnas.1500439112.
Protein disulfide isomerase (PDI) is a chaperone protein in the endoplasmic reticulum that is up-regulated in mouse models of, and brains of patients with, neurodegenerative diseases involving protein misfolding. PDI's role in these diseases, however, is not fully understood. Here, we report the discovery of a reversible, neuroprotective lead optimized compound (LOC)14, that acts as a modulator of PDI. LOC14 was identified using a high-throughput screen of ∼10,000 lead-optimized compounds for potent rescue of viability of PC12 cells expressing mutant huntingtin protein, followed by an evaluation of compounds on PDI reductase activity in an in vitro screen. Isothermal titration calorimetry and fluorescence experiments revealed that binding to PDI was reversible with a Kd of 62 nM, suggesting LOC14 to be the most potent PDI inhibitor reported to date. Using 2D heteronuclear single quantum correlation NMR experiments, we were able to map the binding site of LOC14 as being adjacent to the active site and to observe that binding of LOC14 forces PDI to adopt an oxidized conformation. Furthermore, we found that LOC14-induced oxidation of PDI has a neuroprotective effect not only in cell culture, but also in corticostriatal brain slice cultures. LOC14 exhibited high stability in mouse liver microsomes and blood plasma, low intrinsic microsome clearance, and low plasma-protein binding. These results suggest that LOC14 is a promising lead compound to evaluate the potential therapeutic effects of modulating PDI in animal models of disease.
Protein Disulfide Isomerase A3 Regulates Influenza Neuraminidase Activity and Influenza Burden in the Lung
Int J Mol Sci 2022 Jan 19;23(3):1078.PMID:35162999DOI:10.3390/ijms23031078.
Influenza (IAV) neuraminidase (NA) is a glycoprotein required for the viral exit from the cell. NA requires disulfide bonds for proper function. We have recently demonstrated that protein disulfide isomerase (PDI)A3 is required for oxidative folding of IAV hemagglutinin (HA), and viral propagation. However, it not known whether PDIs are required for NA maturation or if these interactions represent a putative target for the treatment of influenza infection. We sought to determine whether PDIA3 is required for disulfide bonds of NA, its activity, and propagation of the virus. Requirement of disulfides for NA oligomerization and activity were determined using biotin switch and redox assays in WT and PDIA3-/- in A549 cells. A PDI specific inhibitor (LOC14) was utilized to determine the requirement of PDIs in NA activity, IAV burden, and inflammatory response in A549 and primary mouse tracheal epithelial cells. Mice were treated with the inhibitor LOC14 and subsequently examined for IAV burden, NA activity, cytokine, and immune response. IAV-NA interacts with PDIA3 and this interaction is required for NA activity. PDIA3 ablation or inhibition decreased NA activity, viral burden, and inflammatory response in lung epithelial cells. LOC14 treatment significantly attenuated the influenza-induced inflammatory response in mice including the overall viral burden. These results provide evidence for PDIA3 inhibition suppressing NA activity, potentially providing a novel platform for host-targeted antiviral therapies.
Venezuelan equine encephalitis virus E1 protein interacts with PDIA6 and PDI inhibition reduces alphavirus production
Antiviral Res 2023 Apr;212:105560.PMID:36822370DOI:10.1016/j.antiviral.2023.105560.
Venezuelan equine encephalitis virus (VEEV) is an alphavirus transmitted by mosquitos that can cause a febrile illness and induce severe neurological complications in humans and equine populations. Currently there are no FDA approved vaccines or antiviral treatments to combat VEEV. Proteomic techniques were utilized to create an interactome of the E1 fusion glycoprotein of VEEV. VEEV E1 interacted with a number of cellular chaperone proteins including protein disulfide isomerase family A member 6 (PDIA6). PDI inhibition through LOC14 and/or nitazoxanide treatment effectively decreased production of VEEV and other alphaviruses in vitro, including eastern equine encephalitis virus, Sindbis virus, and chikungunya virus. Decreased oxidoreductive capabilities of PDIs through LOC14 or nitazoxanide treatment impacted both early and late events in viral replication, including the production of non-infectious virions and decreased VEEV E1 disulfide bond formation. Results from this study identified PDIs as critical regulators of alphavirus replication and potential therapeutic targets.