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Compositions and methods for modulating c-rel-dependent cytokine production

a technology of c-rel-dependent cytokine and cytokine, which is applied in the field of modulating crel-dependent cytokine production, can solve the problems of excessive pro-inflammatory cytokine production and subsequent excessive production, and achieve the effects of reducing the level of icsbp, and reducing the level of p50 in the nucleus

Inactive Publication Date: 2008-09-18
SYNTA PHARMA CORP
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This approach allows for selective inhibition or modulation of c-Rel-dependent cytokine production, providing a potential therapeutic strategy for autoimmune and inflammatory diseases by targeting c-Rel activity without affecting NFκB and IκB levels.

Problems solved by technology

It is presumed that after an infective or inflammatory stimulus that provokes IL-12 production, the powerful feedback loop promotes IL-12-induced IFN-γ to further augment IL-12 production, leading to consequent excessive production of pro-inflammatory cytokines.

Method used

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  • Compositions and methods for modulating c-rel-dependent cytokine production
  • Compositions and methods for modulating c-rel-dependent cytokine production
  • Compositions and methods for modulating c-rel-dependent cytokine production

Examples

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examples

I. Measuring the Level of IL-12 p40

[0238]Northern blot analysis was performed to examine the mRNA levels of IL-12 p35 and p40. Human PBMC and the human monocyte cell line THP-1 cells were stimulated with IFN-γ / SAC in the presence or absence of Compound 1. Human PBMC were isolated by centrifugation using Ficoll-Paque (Pharmacia Biotech, Uppsala, Sweden) and prepared in RPMI medium supplemented with 10% fetal calf serum (FCS), 100 U / ml penicillin, and 100 μg / ml streptomycin, in a 96-well plate with 5×105 cells / well. The cells were then primed with IFN-γ (100 U / ml) and followed by 0.01% SAC or 1 μg / ml LPS, in the presence of different concentrations of Compound 2 or other compounds. The test compounds were prepared in DMSO and the final DMSO concentration was adjusted to 0.25% in all cultures, including the compound-free control. Cell-free supernatants were taken 18 h later for the measurement of cytokines. The THP-1 cells were obtained from American Type Culture Collection (Manassas, ...

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Abstract

The present invention is directed to compositions and methods for modulating c-Rel-dependent cytokine production without materially altering the level of expression of NFκB and / or the amount of IκB. The present invention is also directed to screening for modulators of c-Rel activity as determined by assaying for altered subcellular localization of c-Rel but where the level of expression of NFκB and / or the amount of IκB is materially unaltered.

Description

[0001]This application is a divisional application of U.S. patent application Ser. No. 10 / 986,553, filed Nov. 10, 2004, pending, which claims the benefit of U.S. Provisional Patent Application Ser. Nos. 60 / 519,048 and 60 / 519,040, filed Nov. 10, 2003, and Nov. 11, 2003, respectively. All of the foregoing applications are incorporated by reference herein in their entirety.FIELD OF THE INVENTION[0002]The present invention is directed to compositions and methods for modulating c-Rel-dependent cytokine production without materially altering the level of expression of NFκB and / or amount of IκB. The present invention is also directed to screening for modulators of c-Rel activity as determined by assaying for altered subcellular localization of c-Rel but where the level of expression of NFκB and / or amount of IκB is materially unaltered.BACKGROUND OF THE INVENTION[0003]The role of cytokines in the development of autoimmune diseases and inflammatory disorders is well known. Cytokines such as ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): G01N33/53C12Q1/02A61KG01N33/50G01N33/567
CPCG01N2333/54G01N33/5035A61P1/02A61P1/04A61P1/16A61P3/10A61P7/00A61P7/06A61P11/00A61P11/06A61P13/12A61P15/02A61P17/00A61P17/02A61P17/06A61P17/14A61P19/00A61P19/02A61P19/10A61P21/04A61P25/00A61P25/06A61P25/14A61P25/16A61P25/28A61P25/32A61P27/02A61P27/16A61P29/00A61P37/00A61P37/02A61P37/06G01N33/6872G01N2333/4703G01N2500/10
Inventor LU, RONGZHENBARSOUM, JAMESWADA, YUMIKO
Owner SYNTA PHARMA CORP
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