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None-hydrophobic compounds for use in treating metastasis and/or cartilage defect

A non-hydrophobic, compound technology, applied in the direction of heterocyclic compound active ingredients, drug combination, drug delivery, etc., can solve the problem of not being able to take it orally

Inactive Publication Date: 2018-03-27
FRIEDRICH ALEXANDER UNIV ERLANGEN NUERNBERG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, peptides are often poor drug candidates because they are easily degraded by proteases in the digestive tract or in the serum, and thus are usually not orally available

Method used

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  • None-hydrophobic compounds for use in treating metastasis and/or cartilage defect
  • None-hydrophobic compounds for use in treating metastasis and/or cartilage defect
  • None-hydrophobic compounds for use in treating metastasis and/or cartilage defect

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Experimental program
Comparison scheme
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Embodiment 1

[0195] Small, fragment-sized compounds of the invention that inhibit MIA were identified using fragment-based in silico screening. In vitro screening of proposed structures was performed and modular synthesis strategies were developed for the most promising molecules.

[0196] NMR titration experiment

[0197] From pairing with AR71 (peptide with amino acid sequence FHWRYPLPLPGQ) 15 HSQC titration of N-labeled MIA revealed that amino acids CYS17, SER18, TYR47, GLY66, ASP67, LEU76, TRP102, ASP103, and CYS106 exhibit strong displacement perturbations (Schmidt, J., A. Riechers, and A.K. Bosserhoff, MIA-a new target protein for malignant melanoma therapy. Histol Histopathol, 2013.28(4): p. 421-426), and defined as interacting residues in in silico protein-peptide docking of MIA and AR71. The resulting model shows that the peptide is bound in a hydrophobic cleft that forms part of the dimerization domain.

[0198] virtual screening

[0199] Use of human MIA protein 1I1J high-r...

Embodiment 2

[0205] Such as Figure 4 Boyden chamber migration assay using human Mel-Im melanoma cells in the presence of compounds 1, 2, 3, 4, 5 and 6 at a concentration of 1 μM (Stoll, R., Lodermeyer, S. & Bosserhoff, A.K. Detailed analysis of MIA protein by mutagenesis. Biol Chem 387, 1601-1606, (2006)) demonstrated a reduction in MIA activity in melanoma cell migration.

[0206] The melanoma cell line Mel-Im (generously gifted by Dr. Johnson, University of Munich, Germany) established from human metastatic biopsy samples was used for Boyden chamber migration assays. All cells were maintained in DMEM ( PAA, Pasching, Germany) and distributed in a ratio of 1:6 every three days. Migration assays were performed in Boyden chambers containing polycarbonate filters with 8-μm pore size (Neuro Probe, Gaithersburg, MD, USA) essentially as described. Add MIA to the cell suspension at a final concentration of 200 ng / mL. Selected compounds were used at a final concentration of 1 μM. Experiment...

Embodiment 3

[0208] In order to assess whether the compounds of the present invention have any adverse effects on normal cells, similar to previous studies (Schmidt, J., et al., Targeting melanoma metastasis and immunosuppression with a newmode of melanoma inhibitory activity (MIA) protein inhibition.PLoS One, 2012.7( 5): page e37941; Riechers, A., et al., Heterogeneous transition metal-based fluorescence polarization (HTFP) assay for probing protein interactions.Biotechniques, 2009.47 (4): pages 837 to 844), using compounds 1, 2, and 3, respectively , 4, 5 and 6 treated human fibroblasts and kidney cells in vitro at a concentration of 7.8 μM. In the presence of the compound, human fibroblasts ( Figure 5 A) and kidney cells ( Figure 5 C) Proliferation and cell adhesion of the same cell type ( Figure 5 B and 5D) No adverse effects.

[0209] Such as Figure 6 As shown, a significant decrease in the proliferation of the human melanoma cell line Mel Im was observed after treatment with ...

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Abstract

The present invention is directed to compounds, tautomers, stereoisomers, and chemically modified compounds thereof, and their use in preventing and / or treating tumors of metastasis and / or cartilage defect, and to a pharmaceutical composition comprising such compound.

Description

[0001] The present invention relates to non-hydrophobic compounds, their use in the prevention and / or treatment of metastasis and / or cartilage defects, and pharmaceutical compositions comprising such compounds, wherein the compounds or compositions are administered eg orally. Background technique [0002] Malignant melanoma is the skin cancer with the highest mortality rate. It is characterized by an early onset of metastases formation and rapid disease progression; in the case of systemic metastases, the five-year survival rate is less than 10% (Balch, C.M., et al., Prognostic Factors Analysis of 17,600 Melanoma Patients: Validation of the American Joint Committee on Cancer Melanoma Staging System. Journal of Clinical Oncology, 2001.19(16): pp. 3622-3634). In the Top5 EU countries (Germany, UK, France, Spain, Italy), USA, and Australia, 125,000 primary neoplastic episodes were diagnosed in 2010; an increase of 150,000 is expected by 2025 (Globocan 2008). As the incidence of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/138A61K31/341A61K31/381A61K31/4164A61K31/4196A61K31/425A61K31/426A61K31/435A61K31/497A61K31/4985A61K31/505A61K31/517A61K31/53A61K31/5375A61P35/00
CPCA61K45/06A61K31/138A61K31/341A61K31/381A61K31/4164A61K31/4196A61K31/425A61K31/426A61K31/435A61K31/47A61K31/496A61K31/497A61K31/4985A61K31/505A61K31/513A61K31/517A61K31/519A61K31/53A61K31/5375A61K31/4184A61P35/04A61K31/197A61K31/40A61K31/4025A61K31/4152A61K31/4402A61K31/4453A61K31/4704A61K31/472A61K31/498A61K31/501A61K31/506A61K31/52A61K31/5377A61K31/55A61K9/0053
Inventor 安雅-卡特林·博塞尔霍夫亚历山大·里歇斯布克哈德·柯尼希曼努埃尔·鲍谢法比安·劳舍尔
Owner FRIEDRICH ALEXANDER UNIV ERLANGEN NUERNBERG
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