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Treatment of diseases and conditions mediated by increased phosphorylation

a technology of phosphorylation and disease, applied in the direction of antibacterial agents, peptide/protein ingredients, immunological disorders, etc., can solve the problems of inability to fully understand, so as to reduce the amount of atp and phosphate groups available, inhibit the effect of increased phosphorylation and increased phosphorylation

Inactive Publication Date: 2011-09-29
AMPIO PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This approach effectively inhibits increased phosphorylation, reducing the severity of diseases and conditions like inflammation and cancer, without requiring knowledge of the specific kinases involved, and can be targeted to specific cells or tissues to minimize side effects.

Problems solved by technology

Also, the very features described above which make kinases so useful in signal transduction, and which have made them evolve to become central to almost every cellular function, also make them extremely difficult to study and understand.
Unfortunately, the enormous number of kinases and the similarities between them have frustrated the discovery and design of specific inhibitors.
Further, because the kinase networks are highly degenerate and interconnected in unknown ways, there is considerable uncertainty with regard to which kinases should be targeted for inhibition to treat many diseases.
Moreover, it is by no means clear that a specific inhibitor of a given kinase will have any effect on a given disease.
Since kinases can be highly promiscuous, there is a significant chance that inhibiting one kinase will simply force another kinase to take its place.

Method used

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  • Treatment of diseases and conditions mediated by increased phosphorylation

Examples

Experimental program
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Effect test

example 1

Inhibition of IL-8 By Dephosphorylated Phosvitin

[0216]Phosvitin was extracted from the yolks of chicken eggs as described by Losso and Nakai, in Egg Uses And Processing Technologies: New Developments, pages 150-157 (Sim and Nakai, eds., Cab International, Oxon, UK, 1994). It was dephosphorylated as described by Reimerdes and Klostermeyer, in Methods in Enzymology, Volume 45, pages 26-28 (1976). This phosvitin preparation was estimated to be about 20-50% dephosphorylated.

[0217]Chicken phosvitin was also purchased from Sigma Chemical Co., St. Louis, Mo., as was bovine serum albumin (BSA; BUS grade=low fatty acid and IgO). Each was used as received from the manufacturer without dephosphorylation.

[0218]Jurkat cells (American Type Culture Collection (ATCC), Rockville, Md.) were cultured (1×106 cells per 0.5 ml culture) in IMDM culture medium (ATCC) containing insulin transferrin selenite solution (ITSS; Sigma) with and without phosvitin or BSA at 37° C., 5% CO2, for 30 minutes. Then, pho...

example 2

Use of Dephosphorylated Phosvitin to Treat Inflammation

[0221]Chicken phosvitin (Sigma) in distilled water (0.5 g / 100 ml) was dephosphorylated by adding 0.4 N NaOH at 37° C. for 3 hours as described in Jiang et al., J. Agric. Food Chem., 48:990-994 (2000). After dephosphorylation, the pH of the phosvitin solution was adjusted to 7.8 with 0.1 N HCl. This phosvitin preparation was found to be 73% dephosphorylated using a gallium column.

[0222]A cream was prepared by mixing the dephosphorylated phosvitin with 100 ml Eucerin cream (Beiersdorf Inc., Wilton, Conn.) to give a final phosvitin concentration of about 0.25%.

[0223]A human volunteer with a chronic skin lesion (etiology unknown) applied the phosvitin cream to the lesion twice per day for two days. The lesion disappeared completely after this treatment.

[0224]Another human volunteer with chronic skin lesions (diagnosed as atopic dermatitis) applied the phosvitin cream to a lesion on the back twice per day for one week. The treated le...

example 3

Inhibition of IL-8 by Unphosphorylated Kinase Substrates

[0228]Casein kinase I substrate (sequence Arg Arg Lys Asp Leu H is Asp Asp Glu Glu Asp Glu Ala Met Ser Ile Thr Ala [SEQ ID NO:3]) and casein kinase II substrate (sequence Arg Arg Arg Ala Asp Asp Ser Asp [SEQ ID NO:4]) were purchased from Sigma-Aldrich, St. Louis, Mo. Each was used as received from the manufacturer since they were unphosphorylated.

[0229]Jurkat cells (American Type Culture Collection (ATCC), Rockville, Md.) were cultured (2×106 cells per 1.0 ml culture) in IMDM culture medium (ATCC) containing insulin transferrin selenite solution (ITSS; Sigma) with and without each of the casein kinase substrates (50 μg / ml and 100 μg / ml) at 37° C., 10% CO2, for 15 minutes. Then, phorbol-12-myristate-13-acetate (PMA; 100 mg / ml; Sigma) and ionomycin (100 mg / ml; Sigma) were added to stimulate the cells, and the cells were further cultured at 37° C., 5% CO2, for 24 hours.

[0230]Cell culture supernatants were analyzed for IL-8 content...

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Abstract

The invention provides methods for the treatment of diseases and conditions mediated by increased phosphorylation, such as inflammation and cancer. The invention also provides methods for the inhibition of increased phosphorylation in cells, tissues and organs. The methods utilize a phosphate acceptor compound (PAC). The invention also provides products comprising a PAC.

Description

[0001]This invention claims the benefit of priority under 35 U.S.C. §119(e) from U.S. Provisional Application 60 / 429,924, filed Nov. 27, 2002, which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]The invention relates to methods for the treatment of diseases and conditions mediated by increased phosphorylation, such as inflammation and cancer. The invention also relates to methods for the inhibition of increased phosphorylation in cells, tissues and organs. The methods utilize a phosphate acceptor compound (PAC). The invention also relates to products comprising a PAC.BACKGROUND OF THE INVENTION[0003]Signal transduction is the cascade of processes by which an extracellular signal interacts with a receptor at the cell surface to ultimately effect a change in cell functioning. Protein phosphorylation plays a key role in signal transduction. Protein phosphorylation is performed by protein kinases, and virtually all aspects of cell functioning in one way...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/02A61P29/00A61P35/00A61K38/07A61K38/08A61K38/17A61K38/38
CPCA61K38/07A61K38/08A61K38/38A61K38/1709A61K38/1703A61P1/02A61P17/00A61P17/02A61P17/04A61P17/06A61P17/10A61P29/00A61P31/00A61P31/04A61P31/10A61P31/12A61P31/22A61P35/00A61P37/06A61P37/08A61P43/00A61P9/00A61K38/17A61K38/16
Inventor BAR-OR, DAVID
Owner AMPIO PHARMA INC
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