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UPAR-antagonists and uses thereof

A molecular and dimer technology, applied in the field of urokinase-type plasminogen activator receptor inhibitors, can solve the problems that the importance of interaction is not discussed, and achieve the effect of excellent drug properties

Inactive Publication Date: 2013-11-13
IFOM FOND INST FIRC DI ONCOLOGIA MOLECOLARE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the importance of the interaction with VN is well documented (Madsen et al., 2007; Smith et al., 2008) that the interaction is critical for uPAR signaling activity, the in vivo interaction Importance not yet discussed

Method used

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  • UPAR-antagonists and uses thereof
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  • UPAR-antagonists and uses thereof

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Embodiment Construction

[0044] The invention will now be described by way of a non-limiting example with reference to the following figures.

[0045] figure 1 .Sketch showing the forced-proximity concept of the uPAR lock.

[0046] The function of uPAR in extracellular proteolysis mediated by uPA binding can be competitively inhibited by receptor binding to the growth factor-like domain (GFD) of uPA. The somatomodulin B domain (SMB) of VN can be exploited to competitively inhibit the function of uPAR in signal transduction mediated by VN binding. D1, D2 and D3 below are uPAR domains.

[0047] (A) GFD and SMB domains as competitive uPAR antagonists

[0048] Blocking uPAR function using a mixture of isolated GFD and SMB requires two sequential first-order intermolecular binding reactions (1 and 2), and two pathways can be used depending on whether GFD or SMB first binds to the receptor (A and B). The overall stability of the ternary uPAR:GFD:SMB complex and thus receptor inhibition is limited by t...

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Abstract

The invention relates to inhibitors of the urokinase-type plasminogen activator receptor (uPAR). The generated inhibitors are bivalent uPAR-ligands containing the receptor binding domains of the extracellular protease urokinase-type plasminogen activator (uPA) and of the extracellular matrix protein vitronectin (VN), in different configurations, linked by a scaffold. The present invention also refers to the above molecules for use as a medicament, in particular for treatment of cancer, and for diagnostic purposes.

Description

technical field [0001] The present invention relates to inhibitors of urokinase-type plasminogen activator receptor (uPAR). The resulting inhibitor is a bivalent uPAR ligand containing different configurations of the extracellular protease urokinase-type plasminogen activator (uPA) and the extracellular matrix protein vitronectin (VN) linked by a scaffold receptor binding domain. Binding of this inhibitor to uPAR forms a complex in which the binding sites for uPA and VN are simultaneously occupied, thereby effectively blocking the proteolytic and signal transduction activities of the receptor. Background technique [0002] Urokinase-type plasminogen activator receptor (uPAR, also known as CD87) is a membrane glycoprotein anchored to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor. A wealth of in vitro, in vivo, and clinical evidence indicates that uPAR plays an important role in a wide range of pathological processes, including tumor growth, invasion, an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/49
CPCC07K2319/00A61K47/481A61K38/00C07K14/78C07K2318/10C12N9/50C07K2319/30A61K45/06A61K47/55A61P35/00C12N9/64
Inventor N·西顿纽斯
Owner IFOM FOND INST FIRC DI ONCOLOGIA MOLECOLARE
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