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Inhibitors of extracellular hsp90

A technology of inhibitors and cells, applied in the special field of molecular therapy that depends on functional extracellular Hps90, extracellular Hsp90 function, can solve problems such as deficiency and toxicity

Inactive Publication Date: 2006-11-08
TUFTS UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the teaching of WO 00 / 53169 only relates to the inhibition of the intercellular Hsp90 protein
[0007] Inhibitors such as the geldanamycin analogue 17-AAG have been tested in clinical trials, but there are toxicity problems due to non-specific inhibition of the protein across all cellular compartments (Dunn (2002) J. Natl. Cancer Inst 94, 1194-5)
Furthermore, the lack of understanding of the interactions between Hsp90 and its client proteins in a variety of cellular signaling processes makes it potentially dangerous to inhibit intracellular Hsp90 with toxic inhibitors

Method used

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Embodiment Construction

[0053] For a more complete understanding of the present invention, the following detailed description is provided.

[0054] The present invention relates to inhibitors that can specifically bind extracellular Hsp90 or, more specifically, can inhibit the function of Hsp90 that is related to the invasiveness and / or metastatic potential of cancer cells. Inhibitors of extracellular Hsp90 are preferably substantially unable to enter the cell or are modified in such a way that the modification substantially inhibits their cellular uptake. Modification of the inhibitors of the invention can be achieved by conjugating the inhibitors to naturally occurring macromolecules such as polypeptides, sugars or artificial biocompatible polymers.

[0055] Preferably, an inhibitor of the invention is a bioconjugate with another protein, a solid matrix (e.g., beads), respectively, so that the inhibitor itself forms multimers, or with an inhibitor that will enhance toxicity to the target cell. Bio...

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Abstract

The present invention describes the inhibitors of extracellular Hsp90. The inhibition of extracellular Hsp90 leads to a reduction of the invasiveness of the tumor cells. Furthermore, the invention relates to the use of molecules inhibiting extracellular Hsp90 function for the manufacture of a medicament for the treatment or prevention of invasion and / or metastatic potential of cancer cells.

Description

[0001] This invention was made with government support under CA81668 awarded by the National Institutes of Health. The government has certain rights in the invention. Background of the invention [0002] Malignant tumors shed cells, which migrate to new tissue and give rise to secondary tumors. The process by which secondary tumors arise is called metastasis and is a complex process in which tumor cells colonize at sites distant from the primary tumor. Liotta ((1986) Cancer Res. 46, 1-7) has proposed a three-step hypothesis for the metastatic process: the first step is tumor cell attachment via cell surface receptors. The anchored tumor cells then secrete hydrolytic enzymes or induce host cells to secrete enzymes that locally degrade the matrix. Matrix lysis is most likely to occur in highly localized areas close to the tumor cell surface. The third step is the movement of tumor cells into the stromal regions that are proteolytically altered. Thus, invasion of the matrix i...

Claims

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Application Information

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IPC IPC(8): C07K14/47A61K31/00A61K31/37A61K39/395A61K49/00C07K16/18C07K16/30C12N15/10G01N33/50
CPCA61K31/00A61K31/37A61K49/0004A61K2039/505C07K16/18C07K16/30C07K2317/622G01N33/5008G01N33/5011G01N33/5029G01N33/5091C07K2317/76A61P35/00A61P35/04A61P43/00
Inventor D·G·杰伊B·K·尤斯塔斯T·萨库赖G·贝斯特
Owner TUFTS UNIV
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