Compounds which affect mRNA stability and uses therefor

Details Compounds which affect mRNA stability and uses therefor Compounds which affect mRNA stability and uses therefor

2001-08-15

2003-10-21

Owens, Amelia (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C549S266000

Reexamination Certificate

active

06635671

ABSTRACT:

This invention relates to biologically active compounds and to their use in the treatment and prophylaxis of disease. In particular the invention relates to compounds which affect the stability of mRNA which contain one or more mRNA instability sequences.
Recently, it has become increasingly apparent that the regulation of RNA half-life plays a critical role in the tight control of gene expression and that mRNA degradation is a highly controlled process. RNA instability allows for rapid up- or down-regulation of mRNA transcript levels upon changes in transcription rates. A number of critical cellular factors, e.g. transcription factors such as c-myc, or gene products which are involved in the host immune response such as cytokines, are required to be present only transiently to perform their normal functions. Transient stabilisation of the mRNAs which code for these factors permits accumulation and translation of these messages to express the desired cellular factors when required; whereas, under non-stabilised, normal conditions the rapid turnover rates of these mRNAs effectively limit and “switch off” expression of the cellular factors. However, abnormal regulation of mRNA stabilisation can lead to unwanted build up of cellular factors leading to undesirable cell transformation, e.g. tumour formation, or inappropriate and tissue damaging inflammatory responses.
Although the mechanisms which control mRNA stability are far from understood, sequence regions have been identified in a number of mRNAs, which appear to confer instability on the mRNAs which contain them. These sequence regions are referred to herein as “mRNA instability sequences”. For example, typical mRNA instability sequences are the AREs (AU rich elements), which are found in the 3′UTR (3′ untranslated region) of certain genes including a number of immediate early genes and genes coding for inflammatory cytokines, e.g. IL-1&bgr; and TNF&agr;.
Kastelic et al. (CYTOKINE, Vol. 8, No. 10, (October), 1996: pp751-761) have reported the finding that radicicol analog A, if added to THP-1 cells activated by IFN-Y and LPS, not only inhibited the secretion of IL-1&bgr; but also induced an extremely rapid degradation of IL-1&bgr;, IL-6 and TNF-&agr; mRNA to undetectable levels in 5-8 h, and that this mRNA degradation appears to be mediated through AU-rich regions present in the 3′ untranslated regions of the RNAs which code for these cytokines.
Previously, novel Radicicol analogs (including radicicol analog A), processes for their preparation and their pharmaceutical use were described in European patent application EP 0606044 A, together with known compounds including radicicol, O-methyl radicicol, and the related compound zearelenone and certain analogs of zearelenone. The radicicol analogs and known compounds are described in EP 0606044 A to be useful for the treatment of disorders with an etiology associated with or comprising excessive cytokine release, particularly IL-1&bgr; release, such as rheumatoid arthritis, osteoarthritis, septic shock, psoriasis, atherosclerosis, inflammatory bowel disease, Crohn's disease and asthma.
We have now found that there are other compounds in addition to radicicol analog A which induce degradation of mRNAs and that such compounds may be used for treatment of diseases and medical conditions which involve increased or prolonged stability and expression of such mRNAs. Moreover we have found that radicicol analog A may be used generally to induce degradation of mRNAs besides IL-1&bgr;, IL-6 and TNF-&agr; mRNAs.
Accordingly the present invention provides a compound which induces degradation of mRNA which contains one or more mRNA instability sequences for use as a pharmaceutical, provided the compound is not radicicol analog A.
In a further aspect the invention provides a method for the prophylaxis or treatment of a disease or medical condition having an etiology associated with the increased stability of mRNA which contains one or more mRNA instability sequences, comprising administering to a human or animal patient an effective amount of a compound which induces degradation of the mRNA, provided that the compound is not radicicol analog A when the disease or medical condition is one with an etiology associated with or comprising excessive cytokine release, particularly IL-1&bgr; release, such as rheumatoid arthritis, osteoarthritis, septic shock, psoriasis, atherosclerosis, inflammatory bowel disease, Crohn's disease and asthma.
In a yet further aspect the invention provides use of a compound which induces degradation of mRNA which contains one or more mRNA instability sequences, for the preparation of a medicament for use in the treatment or prophylaxis of a disease or medical condition having an etiology associated with the increased stability of mRNA which contains one or more mRNA instability sequences, provided that the compound is not radicicol analog A when the disease or medical condition is one with an etiology associated with or comprising excessive cytokine release, particularly IL-1&bgr; release, such as rheumatoid arhritis, osteoarthritis, septic shock, psoriasis, atherosclerosis, inflammatory bowel disease, Crohn's disease and asthma.
The invention also provides a method for inducing degradation of mRNA in a patient, which comprises administering an effective amount of a compound which induces mRNA degradation to the patient, wherein the mRNA contains an mRNA instability sequence, provided that the compound is not radicicol analog A when the mRNA is mRNA coding for IL-1&bgr;, IL-6 or TNF-&agr;.
Further the invention provides use of a compound which induces mRNA degradation in the preparation of a medicament for use in inducing degradation of mRNA which contains a mRNA degradation sequence in a patient, provided that the compound is not radicicol analog A when the mRNA is mRNA coding for IL-1&bgr;, IL-6 or TNF-&agr;.
The present invention further provides the use of a radicicol analog for preparation of a medicament for treatment of a cancer and/or malignant disease.
The present invention also provides a method for the prophylaxis or treatment of a cancer and/or malignant disease comprising administering to a patient an effective amount of a radicicol analog.
Any compound which induces degradation of mRNA which contains a mRNA instability sequence is potentially of interest for use in the present invention. Compounds which induce degradation of mRNA which contains a mRNA instability sequence are hereinafter referred to as Compounds for use in the invention. Such compounds include radicicol analogs, in particular radicicol analog A or radicicol; for instance, as described in EP 0606044.
Our copending British patent application no. 9828709.7 describes a reporter gene assay for the identification of compounds which destabilise mRNA. In this assay test compounds are contacted with a DNA expression system which in the absence of the compound is capable of expressing a protein having a detectable signal, and wherein the mRNA which codes for the protein and which is transcribed from the expression system comprises at least one copy of a mRNA instability sequence. The detectable signal is measured in the presence of the test compound and the result obtained is compared with a control. Compounds which destabilise mRNAs induce degradation of the mRNA which codes for the detectable signal leading to a decrease in the magnitude of the detectable signal obtained in the reporter gene assay.
Preferred compounds for use in the present invention include compounds which may be identified as inducers of mRNA instability using the reporter gene assay as described above and as described in more detail in the above mentioned British patent application no. 9828709.7 and as hereinafter described in the Examples. Particular examples of compounds for use in the present invention include radicicol and the radicicol analogs.
Radicicol, the compound of formula I
has been known for many years as a natural compound, e.g. as a metabolite of the microorganism
Monosporium

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