Membrane type-1 matrix metalloprotein inhibitors and uses thereof

一种基质金属、膜型的技术，应用在蛋白酶抑制剂、肽/蛋白质成分、抗炎剂等方向

Inactive Publication Date: 2011-12-28
ANGLACHEM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This process may involve the decomposition of the ECM structure

Method used

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  • Membrane type-1 matrix metalloprotein inhibitors and uses thereof
  • Membrane type-1 matrix metalloprotein inhibitors and uses thereof
  • Membrane type-1 matrix metalloprotein inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0262] Preparation of MT1-MMP-derived peptides

[0263] In carrying out the experiments described in the Examples below, the following peptides were prepared. First, a peptide with the sequence of the cytoplasmic domain of MT1-MMP (RRHGTPRRLLLYCQRSLLDKV; SEQ ID NO: 117) and a non-phosphorylatable form of this peptide (RRHGTPRRLLFCQRSLLDKV; SEQ ID NO: 118) were prepared, wherein in combination with human MT1- The tyrosine at the position corresponding to amino acid 573 of the MMP sequence was replaced by phenylalanine. This non-phosphorylatable peptide was referred to as "M-14".

[0264] Additionally, a peptide with the M-14 sequence fused to the third helix of the cell-penetrating tentaclepedin homology domain (RQIKIWFQNRRMKWKK; SEQ ID NO: 119) was made. This fusion peptide is called ACM-14 and has the sequence: Biotin-Ahx-RQIKIWFQNRRMKWKK-RRHGTPRRLLFCQRSLLDKV (SEQ ID NO: 176). A version of the fusion peptide in which the cytoplasmic MT1-MMP domain sequence was scrambled wa...

Embodiment 2

[0266] Expression of Y573F MT1-MMP inhibits tumor growth

[0267] HT1080 fibrosarcoma cells were stably transfected with WT MT1-MMP or Y573F MT1-MMP. HT1080 cells are very aggressive cancer cells that express elevated levels of MT1-MMP. These two groups of cells were transplanted subcutaneously into athymic nude mice, and tumor growth was monitored. Such as figure 2 As shown, cells expressing the cytoplasmic domain of MT1-MMP exhibited significant tumor growth, whereas no tumor growth was observed in mice receiving cells expressing the Y573F mutant.

Embodiment 3

[0269] ACM-14 and scACM-14 efficiently taken up by fibrosarcoma cells

[0270] To determine whether ACM-14 and scACM-14 were able to enter tumor cells, HT-1080 fibrosarcoma cells were incubated with each peptide (1 μM) for 1 hr, and peptide uptake was analyzed by immunofluorescence and confocal microscopy. Such as image 3 As shown, ACM-14 and its promiscuous form (scACM-14) were visualized in this cell, indicating efficient and rapid cellular uptake.

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Abstract

Based on the discovery that a soluble polypeptide including a nonphosphorylatable form of the MT1-MMP cytoplasmic domain is capable of inhibiting MT1-MMP in a dominant negative manner, the present invention provides compositions including MT1-MMP inhibitors such as peptide inhibitors, and methods for treating diseases associated with MT1-MMP activity. Such diseases include cancer, arthritis, and heart disease, and vascular disease.

Description

technical field [0001] The present invention relates to compounds capable of inhibiting membrane type-1 metalloprotease (MT1-MMP or MMP-14), and methods of using these compounds to treat diseases such as cancer, heart and vascular diseases, and arthritis. Background technique [0002] Disease processes, including cancer, cardiac and vascular diseases, and arthritis, involve the breakdown and remodeling of the extracellular matrix (ECM). [0003] Cancer is a disease marked by the uncontrolled growth of abnormal cells. Cancer cells overcome the barriers imposed on normal cells with a limited lifespan to grow indefinitely. As cancer cells continue to grow, genetic changes may continue to occur until the cancer cells exhibit a more aggressive growth phenotype. If left untreated, metastasis, the spread of cancer cells to distant areas of the body through the lymphatic system or bloodstream, can then damage healthy tissue. [0004] Cancer metastasis requires that cancer cells l...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N9/64A61K38/10A61K38/48A61K38/57A61P19/02A61P35/00C07K14/81
CPCC12N9/6491A61K38/4886A61P9/00A61P9/10A61P9/12A61P19/02A61P19/08A61P29/00A61P35/00A61P35/02
Inventor 理查德·贝利沃丹尼斯·金格拉斯卡里纳·恩亚伦多
Owner ANGLACHEM INC
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