Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1997-08-08
1998-12-15
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
552502, 552506, 552510, 552511, 4352541, A61K 3100
Patent
active
058497242
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a strain of microorganism and to new compounds exhibiting farnesyl transferase-inhibiting properties.
Various genes, called proto-oncogenes and suppressor genes, are involved in the control of cell division. Among these, the ras genes and their products, generally designated Ras proteins, play a key role in the control of cell proliferation in all the eukaryotic organisms where they have been sought out. In particular, it has been shown that certain specific modifications of these proteins cause them to lose their normal control and lead them to become oncogenic. Accordingly, a large number of human tumours (about 10 to 30%) have been associated with the presence of modified ras genes.
The elucidation of the exact role of these Ras proteins in cells, the way they function and their characteristics therefore constitutes a major factor for the understanding of and the therapeutic approach to carcinogenesis.
The corresponding protein is synthesized in vivo in the form of a cytosoluble precursor and then post-translationally modified so as to confer its biological activity on it and allow it to transform mammalian cells. The first and necessary stage of these post-translational modifications consists in a farnesylation of the thiol group of a cysteine unit, located at the level of the terminal carbonyl group of Ras. This cysteine unit forms part of the identification sequence for prenylation, CAAX (SEQ ID No. 1), where C represents cysteine, A an aliphatic residue and X any amino acid. It is the protein farnesyl transferase which catalyses the transfer of a farnesyl group from farnesyl diphosphate to the compound CAAX Ras and therefore which confers, at the end of this prenylation, the required biological activity on the protein to transform cells.
The discovery of compounds inhibiting this post-translational modification has quickly emerged as one of the possible means for developing new anticancer treatments. The inhibition of the farnesylation of Ras could block the localization of the Ras protein at the membrane level and could consequently block its ability to transform normal cells into cancerous cells.
The main object of the present invention is to provide new farnesyl transferase inhibitors.
More specifically, the present invention results from the isolation of a strain of microorganism related to the genus Chrysosporium, more preferably to the species lobatum having particularly advantageous properties for the production of compounds manifesting inhibitory properties towards the protein farnesyl transferase.
One aspect of the invention therefore relates to a Chrysosporium strain characterized in that it is the microorganism Chrysosporium CBS 123.95, one of its derivatives or its mutants.
For the purpose of the present invention, derivative or mutant is understood to mean any strain obtained from the strain Chrysaosporium CBS 123.95 and capable of being used for the production of compounds according to the invention and more particularly exhibiting inhibitory properties towards the protein farnesyl transferase. In particular, such derivatives or mutants may be obtained by genetic modifications (alteration at the level of the DNA) or biochemical modifications. To this effect, various mutagenesis tools may be used, such as for example nonspecific tools: and the like), or specific tools such as DNA-directed mutational insertion systems (transposons, retrotransposons, integrative plasmids and the like).
The fermentation by this strain on a suitable culture medium and subsequent extraction of the corresponding fermentation broth makes it possible to isolate compounds which, although having an original structure compared with conventional farnesyl transferase inhibitors, unexpectedly prove to be advantageous in this respect.
The present invention also relates to compounds capable of being obtained by fermentation by the Chrysosporium strain CBS 123.95 or one of its mutants via the extraction of a corresponding fermentation broth.
Another subject of the present invention relat
REFERENCES:
van der Pyl et al., J. Antibiot., 48(7), 736-7, 1995.
Debernard Jean-Jacques
Leboul Jean
Van Der Pyl Didier
Delacroix-Muirheid C.
Martin Michael B.
Parker III Raymond S.
Rhone-Poulenc Rorer S.A.
Tsang Cecilia J.
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