更新于：2024-11-01

αvβ6 x αvβ5 x αvβ3 x α5β1 x αvβ1

更新于：2024-11-01

基本信息

关联

项与 αvβ6 x αvβ5 x αvβ3 x α5β1 x αvβ1 相关的药物

XC-201

靶点

α5β1 x αvβ1 x αvβ3 x αvβ5 x αvβ6

作用机制

α5β1拮抗剂 [+4]

在研机构

xCella Biosciences, Inc.初创企业

原研机构

xCella Biosciences, Inc.初创企业

在研适应症

肿瘤

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

100 项与 αvβ6 x αvβ5 x αvβ3 x α5β1 x αvβ1 相关的临床结果

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100 项与 αvβ6 x αvβ5 x αvβ3 x α5β1 x αvβ1 相关的转化医学

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0 项与 αvβ6 x αvβ5 x αvβ3 x α5β1 x αvβ1 相关的专利（医药）

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项与 αvβ6 x αvβ5 x αvβ3 x α5β1 x αvβ1 相关的文献（医药）

2021-06-01·Cell Reports1区 · 生物学

Integrin intra-heterodimer affinity inversely correlates with integrin activatability

1区 · 生物学

ArticleOA

作者: Sun, Guangyu ; Holley, Scott A ; Guillon, Emilie

Integrins are heterodimeric cell surface receptors composed of an α and β subunit that mediate cell adhesion to extracellular matrix proteins such as fibronectin. We previously studied integrin α5β1 activation during zebrafish somitogenesis, and in the present study, we characterize the integrin αV fibronectin receptors. Integrins are activated via a conformational change, and we perform single-molecule biophysical measurements of both integrin activation via fluorescence resonance energy transfer (FRET)-fluorescence lifetime imaging microscopy (FLIM) and integrin intra-heterodimer stability via fluorescence cross-correlation spectroscopy (FCCS) in living embryos. We find that integrin heterodimers that exhibit robust cell surface expression, including αVβ3, αVβ5, and αVβ6, are never activated in this in vivo context, even in the presence of fibronectin matrix. In contrast, activatable integrins, such as integrin αVβ1, and alleles of αVβ3, αVβ5, αVβ6 that are biased to the active conformation exhibit poor cell surface expression and have a higher intra-heterodimer dissociation constant (K_D). These observations suggest that a weak integrin intra-heterodimer affinity decreases integrin cell surface stability and increases integrin activatability.

2019-11-01·Journal of Biological Chemistry

A disease-associated mutation in fibrillin-1 differentially regulates integrin-mediated cell adhesion

Article

作者: Liu, Sean ; Jensen, Sacha A ; DeGrado, William ; Handford, Penny A ; Reed, Nilgun Isik ; Del Cid, Joselyn S ; Sundaram, Aparna B ; Molnar, Kathleen ; Dang, Bobo ; Sheppard, Dean

Fibrillins serve as scaffolds for the assembly of elastic fibers that contribute to the maintenance of tissue homeostasis and regulate growth factor signaling in the extracellular space. Fibrillin-1 is a modular glycoprotein that includes 7 latent transforming growth factor β (TGFβ)-binding protein-like (TB) domains and mediates cell adhesion through integrin binding to the RGD motif in its 4th TB domain. A subset of missense mutations within TB4 cause stiff skin syndrome (SSS), a rare autosomal dominant form of scleroderma. The fibrotic phenotype is thought to be regulated by changes in the ability of fibrillin-1 to mediate integrin binding. We characterized the ability of each RGD-binding integrin to mediate cell adhesion to fibrillin-1 or a disease-causing variant. Our data show that 7 of the 8 RGD-binding integrins can mediate adhesion to fibrillin-1. A single amino acid substitution responsible for SSS (W1570C) markedly inhibited adhesion mediated by integrins α5β1, αvβ5, and αvβ6, partially inhibited adhesion mediated by αvβ1, and did not inhibit adhesion mediated by α8β1 or αIIbβ3. Adhesion mediated by integrin αvβ3 depended on the cell surface expression level. In the SSS mutant background, the presence of a cysteine residue in place of highly conserved tryptophan 1570 alters the conformation of the region containing the exposed RGD sequence within the same domain to differentially affect fibrillin's interactions with distinct RGD-binding integrins.

2016-10-01·Biochemical Pharmacology2区 · 医学

Characterisation of a novel, high affinity and selective αvβ6 integrin RGD-mimetic radioligand

2区 · 医学

Article

作者: Bibby, Lloyd I ; Hall, Eleanor R ; Slack, Robert J

The alpha-v beta-6 (αvβ6) integrin has been identified as playing a key role in the activation of transforming growth factor-β (TGFβ) that is hypothesised to be pivotal in the development of cancer and fibrotic diseases. Therefore, the αvβ6 integrin is an attractive therapeutic target for these debilitating diseases and a drug discovery programme to identify small molecule αvβ6 selective arginyl-glycinyl-aspartic acid (RGD)-mimetics was initiated within GlaxoSmithKline. The primary aim of this study was to pharmacologically characterise the binding to αvβ6 of a novel clinical candidate, compound 1, using a radiolabelled form. Radioligand binding studies were completed with [(3)H]compound 1 against the human and mouse soluble protein forms of αvβ6 to determine accurate affinity estimates and binding kinetics. The selectivity of compound 1 for the RGD integrin family was also determined using saturation binding studies (αvβ1, αvβ3, αvβ5, αvβ8, α5β1 and α8β1 integrins) and fibrinogen-induced platelet aggregation (αIIbβ3 integrin). In addition, the relationship between divalent metal cation type and concentration and αvβ6 RGD site binding was also investigated. Compound 1 has been demonstrated to bind with extremely high affinity and selectivity for the αvβ6 integrin and has the potential as a clinical tool and therapeutic for investigating the role of αvβ6 in a range of disease states both pre-clinically and clinically. In addition, this is the first study that has successfully applied radioligand binding to the RGD integrin field to accurately determine the affinity and selectivity profile of a small molecule RGD-mimetic.