预约演示

更新于：2025-01-23

CRAC x IL-2

更新于：2025-01-23

基本信息

关联

项与 CRAC x IL-2 相关的药物

IL-2/CRAC inhibitors(Lupin)

靶点

CRAC x IL-2

作用机制

CRAC抑制剂 [+1]

在研机构

Lupin Ltd

原研机构

Lupin Ltd

在研适应症

类风湿关节炎

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 CRAC x IL-2 相关的临床试验

ChiCTR2300072174

/ CompletedN/A

The efficacy of calcium ion channel blocker combined proton pump inhibitors for the treatment of Nutcracker esophagus - CCB combined PPIs for the treatment of NE

开始日期2016-12-16

申办/合作机构-

100 项与 CRAC x IL-2 相关的临床结果

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100 项与 CRAC x IL-2 相关的转化医学

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0 项与 CRAC x IL-2 相关的专利（医药）

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项与 CRAC x IL-2 相关的文献（医药）

2022-05-01·Journal of Ethnopharmacology2区 · 医学

In-vitro and in-vivo anti-allergic effects of magnolol on allergic rhinitis via inhibition of ORAI1 and ANO1 channels

2区 · 医学

Article

作者: Nam, Joo Hyun ; Kim, Woo Kyung ; Nam, Yu Ran ; Woo, Joo Han ; NamKung, Wan ; Kim, Hyun Jong ; Phan, Hong Thi Lam

ETHNOPHARMACOLOGICAL RELEVANCEFlos Magnoliae (the dried flower buds of Magnolia biondii Pamp, FM) is a known herbal traditional medicine used for the symptomatic relief of nasal congestion and rhinorrhea caused by rhinitis and sinusitis. Magnolol, a neolignan from the magnolia family, is a secondary metabolite known to have anti-allergic and anti-inflammatory effects. However, the underlying mechanisms and therapeutic effect of magnolol in the treatment of allergic rhinitis (AR) remain elusive.AIMS OF THE STUDYAnoctamin 1 (ANO1), a calcium-activated anion channel, mediates mucus and electrolyte secretion in nasal airway epithelial cells, whereas calcium release-activated calcium channel protein 1 (ORAI1) participates in the activation of T-lymphocytes and mast cells. The aim of our study is to understand the mechanisms of action of magnolol against AR, i.e., whether it acts through the modulation of ANO1 and ORAI1 channels that are expressed in nasal epithelial cells and T-lymphocytes, respectively.MATERIALS AND METHODSWhole-cell patch clamp was used to record the activity of ORAI1 and ANO1 ion channels in ORAI1 or ANO1 overexpressed HEK293T cells, while the Ussing chamber apparatus was used to measure electrolyte transport via the epithelium, in Calu-3 cells cultured in an air-liquid interface. Additionally, calcium imaging of Jurkat T-lymphocytes was used to assess changes in the intracellular calcium concentration. Magnolol toxicity was assessed using the CCK-8 assay, and its effect on T-lymphocyte proliferation was measured by labeling human primary T-lymphocytes with carboxyfluorescein succinimidyl ester. Finally, OVA-induced Balb/c mice were employed to evaluate the effect of magnolol on nasal symptoms, as well as cytokine and eosinophil infiltration in AR.RESULTSMagnolol inhibits ORAI1 and ANO1 channels in a concentration-dependent manner. Magnolol (30 μM) inhibits anti-CD3 induced cellular proliferation and production of IL-2 via ORAI1 channels in T-lymphocytes. Further, ATP-induced electrolyte transport mediated by ANO1 channels is significantly inhibited by magnolol in IL-4 sensitized Calu-3 cells. Notably, 300 μM magnolol significantly attenuates cytokine and eosinophil infiltration, thus alleviating AR symptoms in mice OVA-induced AR.CONCLUSIONMagnolol may be a promising therapeutic agent for the treatment and prevention of AR.

2021-12-09·Journal of Medicinal Chemistry1区 · 医学

Discovery of a Novel Potent and Selective Calcium Release-Activated Calcium Channel Inhibitor: 2,6-Difluoro-N-(2′-methyl-3′-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)benzamide. Structure–Activity Relationship and Preclinical Characterization

1区 · 医学

Article

作者: Kumar, Swaroop ; Daler, Jagadeesh ; Nemade, Harshal Narendra ; Pareek, Himani ; Naik, Kumar ; Jachak, Santosh ; Mehta, Maneesh ; Deshmukh, Gokul ; Kanoje, Vijay ; Yeshodharan, Rajesh ; Bhonde, Mandar ; Narasimham, Lakshmi ; Irlapatti, Nageswara Rao ; Karche, Vijay ; Kamalakannan, Prabakaran ; Bokan, Sanjay ; Budhe, Sagar ; Nigade, Prashant ; Gholve, Milind ; Ingawale, Sachin ; Kalia, Anil ; Bhankhede, Trupti ; Phukan, Samiron ; Kizhakinagath, Praveenkumar Anidil ; Dadke, Disha ; Patil, Vinod ; Gundu, Jaysagar ; Singh, Minakshi ; Sindkhedkar, Milind ; Ahirrao, Prajakta ; Shah, Chirag ; Sharma, Sharad ; Sinha, Neelima ; Kumar, Hemant ; Tamane, Kaustubh ; Khedkar, Nilesh Raghunath ; Modi, Dipak ; Shankar, Rajesh ; Kamboj, Rajender Kumar ; Bakhle, Dhananjay ; Pawar, Shashikant ; Shinde, Vikas ; Patil, Amit ; Gupta, Rajesh ; Shaikh, Zubair ; Padiya, Kamlesh J. ; Palle, Venkata P. ; Mallurwar, Sadanand ; Nemmani, Kumar V. S. ; Venugopal, Spinvin ; Pandey, Dilip ; Kuldharan, Sandip ; George, Shaji K. ; Sharma, Nidhi ; Vishwase, Gururaj ; Wagh, Akshaya

The role of calcium release-activated calcium (CRAC) channels is well characterized and is of particular importance in T-cell function. CRAC channels are involved in the pathogenesis of several autoimmune diseases, making it an attractive therapeutic target for treating inflammatory diseases, like rheumatoid arthritis (RA). A systematic structure-activity relationship study with the goal of optimizing lipophilicity successfully yielded two lead compounds, 36 and 37. Both compounds showed decent potency and selectivity and a remarkable pharmacokinetic profile. Further characterization in in vivo RA models and subsequent histopathological evaluation of tissues led to the identification of 36 as a clinical candidate. Compound 36 displayed an excellent safety profile and had a sufficient safety margin to qualify it for use in human testing. Oral administration of 36 in Phase 1 clinical study in healthy volunteers established favorable safety, tolerability, and good target engagement as measured by levels of IL-2 and TNF-α.

2016-09-01·Life Sciences3区 · 医学

CRAC channels are required for [Ca2+]i oscillations and c-fos gene expression after muscarinic acetylcholine receptor activation in leukemic T cells

3区 · 医学

Article

作者: Yurie, Yukako ; Fujii, Takeshi ; Kawashima, Koichiro ; Mashimo, Masato

AIMST lymphocytes express muscarinic acetylcholine receptors (mAChRs) involved in regulating their proliferation, differentiation and cytokine release. Activation of M1, M3 or M5 mAChRs increases the intracellular Ca(2+) concentration ([Ca(2+)]i) through inositol-1,4,5-phosphate (IP3)-mediated Ca(2+) release from endoplasmic reticulum Ca(2+) stores. In addition, T lymphocytes express Ca(2+)-release activated Ca(2+) (CRAC) channels to induce Ca(2+) influx and to regulate diverse immune functions. Our aim in the present study was to assess the role of CRAC channels during mAChR activation in the Ca(2+)-dependent transduction that contributes to the regulation of T cell function.MAIN METHODSChanges in [Ca(2+)]i following mAChR activation on human leukemic T cells, CCRF-CEM (CEM), were monitored using fura-2, based on the ratio of 510nm fluorescences elicited by excitation at 340nm and 380nm (R340/380).KEY FINDINGSWe demonstrate that CEM cells express mainly M3 and M5 mAChRs, but little the M1 subtype, and that oxotremorine-M (Oxo-M), an mAChR agonist, induces an initial transient increase in [Ca(2+)]i followed by repetitive [Ca(2+)]i oscillations. Removing extracellular Ca(2+) or pharmacological blockade of CRAC channels abolished the [Ca(2+)]i oscillations without affecting the initial [Ca(2+)]i transient induced by Oxo-M. Moreover, CRAC channel blockade also suppressed Oxo-M-induced c-fos and interleukin-2 expression.SIGNIFICANCEThese results suggest that upon M3 or M5 mAChR activation, IP3-mediated Ca(2+) release induces extracellular Ca(2+) influx through CRAC channels, which generates repetitive [Ca(2+)]i oscillations and, in turn, enhances c-fos gene expression in T lymphocytes.

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