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WO1996005220A1 - Composes utilises dans le traitement des carcinomes - Google Patents

Composes utilises dans le traitement des carcinomes Download PDF

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Publication number
WO1996005220A1
WO1996005220A1 PCT/GB1995/001892 GB9501892W WO9605220A1 WO 1996005220 A1 WO1996005220 A1 WO 1996005220A1 GB 9501892 W GB9501892 W GB 9501892W WO 9605220 A1 WO9605220 A1 WO 9605220A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino acid
residue
negatively charged
xaa
glu
Prior art date
Application number
PCT/GB1995/001892
Other languages
English (en)
Inventor
Denis Raymond Stanworth
Valerie Jones
Original Assignee
Peptide Therapeutics Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Peptide Therapeutics Limited filed Critical Peptide Therapeutics Limited
Priority to AU32266/95A priority Critical patent/AU3226695A/en
Publication of WO1996005220A1 publication Critical patent/WO1996005220A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0819—Tripeptides with the first amino acid being acidic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to compounds, particularly a class of peptides for use in the treatment of carcinomas.
  • Amino acids and amino acid residues are represented herein by their standard codes as identified by IUPAC-IUB Biochemical Nomenclature Commission and represent D and L amino acids, their analogues or derivatives.
  • mast cells are known to participate in the development of anaphylaxis mediated by IgE.
  • Ionov suggested that the ability of mast cell inhibitors to impede tumour growth is connected with the inhibition of anaphylactic reactions in tumour-bearing organisms.
  • IgE antibodies specific to tumour antigens appear in an organism. These antibodies induce anaphylactic reactions at the line of demarcation between tumour and healthy tissues. This has been confirmed by finding degranulation of mast cells at their sites of contact with tumour cells and by elevated histamine concentrations in tumour bearing animals. Ionov presumes these anaphylactic reactions are able to promote tumour growth.
  • mast cell-stabilising agent (Fisons FPL 55618) had significant benefits in reducing tumour growth of rat mammary adenocarcinoma in vivo. This observation supports the concept that mast cell/tumour cell interactions are important for the growth and invasive properties of the model breast carcinoma used.
  • carcinoma proliferation especially that of mammary adenocarcinoma can be treated by inhibiting mast cell degranulation mediated by IgE, by administering compounds which can neutralise, block or reduce triggering of the release of histamine by the action of IgE on mast cells.
  • the present inventors have found that the compounds of the type described by Stanworth can be used to treat carcinomas.
  • the treatment is based on the inventors concept of the link between the effect of inhibition of IgE reactions and the effect that mast cell degranulation is inhibited and the consequential effect that carcinoma proliferation is inhibited.
  • This radical approach differs fundamentally from those suggested or hinted at in the prior art in two ways:
  • the invention does not attempt to block the direct consequence of mast cell degranulation (i.e. by histamine- blocking agents) .
  • the invention can provide for the use of compounds, particularly a class of peptides, which prevent "triggering" of histamine release by mast cell degranulation and consequently inhibit carcinoma proliferation.
  • the present invention can provide use of a compound comprising a first negatively charged atom or group and a second negatively charged atom or group, separated by a spacing group effective conformationally to position said negatively charged atoms or groups so that they will neutralise the lysine residues of the amino acid sequence Lys Thr Lys at positions 497-499 of the Ce4 constant domain of human IgE, in the manufacture of a medicament for the treatment of carcinomas, especially mammary adenocarcinomas.
  • the present invention can provide use of a peptide of the following formula I (in which the left-hand side represents the N-terminus and the right-hand side the C- terminus) :
  • R 1 represents a residue of an amino acid or of a sequence of two or more amino acids, which may be the same or different;
  • R 2 represents a residue of an amino acid or of a sequence of two or more amino acids, which may be the same or different; (but preferably any amino acid residue of R 1 or R 2 adjacent to an Xaa residue is neither positively nor negatively charged) ;
  • Xaa 1 represents a residue of a negatively charged amino acid, preferably Glu;
  • Sp represents a spacing residue, preferably of a non-charged amino acid, preferably Pro, or of a non-charged dipeptide, which provides the spacing required for the negatively charged groups of the Xaa residues to be sufficiently proximal to the lysine residues of the amino acid sequence Lys Thr Lys at positions 497-499 of the Ce4 constant domain of human IgE to neutralise them;
  • Xaa 2 represents a residue of a negatively charged amino acid, preferably Glu; and m and n denote the number of amino acids in R 1 and 2 R respectively and each of m and n independently is 0 or an integer of from 1 to 22, and the sum of m plus n is from 0 to 22; and their terminal functional derivatives, in the manufacture of a medicament for the treatment of carcinomas especially mammary adenocarcinomas.
  • the present invention can provide a method of treatment for carcinomas, especially mammary adenocarcinomas, comprising administering an effective dose of the compound, peptide or medicament described herein.
  • terminal functional derivative includes any derivative formed by reaction of the terminal amino or carboxyl group and which does not alter adversely the character imparted to the peptide by the other amino acid residues.
  • any conventional derivative especially N- acetyl and/or C-amide, can be used in this invention.
  • the peptides used in this invention have a length of from 3 to 25 amino acid residues (or spacing equivalent when Sp is not an amino acid or dipeptide residue) , preferably 3 to 20 and most preferably 3 to 10.
  • peptides used in this invention should contain two negatively charged amino acids spaced apart by an appropriate spacer group.
  • the nature of the spacer group is in principle immaterial so long as it performs the function of spacing the negative charges on the negatively charged amino acids, so that they lie adjacent to the positive charges on the lysines of the IgE chain referred to above.
  • the positive charge in lysine lies on the amino group nitrogen atom of a 4-aminobutyl side chain. Computer modelling by the inventors predicts that these nitrogens lie about 1.4 nm apart, and that a range of separations between about 1.0 and 1.5 nm might be effective.
  • the spacing between the negatively charged oxygens in the 2-carboxyethyl side-chains of glutamate is about 1.3 nm.
  • the spacing group is the single amino acid residue proline. If another amino acid were included in the spacing group, i.e. if it were a dipeptide, the spacing between the negative charges on the glutamates would increase by about the length of two C-N bonds, roughly 0.3 nm, to 1.6 nm, which may be a little too great for the best neutralising effect.
  • the spacing group might have to be made correspondingly longer, i.e. usually a dipeptide residue. It would be possible for the peptides to have different negatively charged residues, such as one glutamate and one aspartate, but this particular combination may give rise to some spacing problems as the single amino acid spacer is a little short, while the dipeptide spacer is a little long, although it is likely that the effects of the invention would be obtained in some degree with either. Using these guidelines, the person of average skill in the art will be able to obtain the benefits of this invention for a variety of different peptides.
  • the amino acids herein can have the (D) or (L) configuration, but are preferably selected from the 20 naturally occurring (L-) amino acids.
  • the preferred negatively charged amino acids are aspartic (Asp) or glutamic (Glu) .
  • the spacing group Sp preferably comprises (consists of when it is a single amino acid residue or includes when it is a dipeptide residue) proline (Pro) or a ring-substituted derivative thereof.
  • the peptides are thought to bind to the patient's IgE, after the IgE has supposedly undergone a conformational change thereby blocking its subsequent action of triggering mast cells. Such triggering initiates release of histamine.
  • the two negatively charged amino acid residues should be presented to the IgE. Accordingly, the peptide should not contain any amino acids which are likely to interfere with such presentation or cause the peptide to bind to other proteins.
  • the spacing group preferably does not comprise cysteine, which might cause binding to other proteins.
  • the peptide need not be any longer than a tripeptide, as in preferred peptides Glu Pro Glu and Glu Gly Glu, but it can have additional, flanking amino acid(s) at either or both side of the essential motif Xaa 1 Sp Xaa 2 .
  • any flanking amino acids be the same within each flank or both flanks, e.g. as in another peptide of the invention, having the sequence:
  • peptides of a more natural structure such as that of sequence: Ser His Ala lie Arg Ser lie Thr Glu Pro Glu Thr Ala 1 5 10
  • the peptides of the invention may be prepared by standard methods, e.g. the well-known Fmoc. method.
  • the peptides used in the invention are preferably administered as such, i.e. without any carrier such as a conjugated protein or a branched peptide type of carrier, as it is not desirable that the patient should raise antibodies against them. It may well be desirable, however, that they be administered in a slow release or depot form, for example in liposomes or nanoparticles (isobutyl and isodecylcyanoacrylate carriers used for anti- cancer drugs) .
  • the peptides used in the invention may be administered by any of the conventional routes of giving drugs, for example orally, by intravenous or intramuscular injection or as eyedrops or as a nasal spray.
  • compositions manufactured according to the invention comprise a compound, such as a peptide, and a carrier or diluent.
  • Oral preparations include solid forms such as tablets, pills, lozenges and capsules, and liquid forms such as solutions in containers and sprays, e.g. nasal and throat sprays, all of which can be formulated in any conventional way.
  • Injectable preparations include sterile solutions, especially in physiological saline. If the peptides are readily soluble, they can be administered very easily in a liquid form.
  • each dose typically containing from 0.01 to 1 mg. of the peptide.
  • the Y residue could simply be an aliphatic chain, as in a 1,5-pentylenediamine N,N-di- (3-propionate) , but preferably has some rigidity to mimic the planar carbonyl groups in peptide linkages and possibly additional rigidity as conferred by the pyrrolidine ring in the preferred proline spacer amino acid. This may be provided by at least one carbocyclic or heterocyclic ring within Y, as in 1,2- cyclopentylene and 1,2-pyrrolidinylene compounds or in bicyclic ring systems.
  • the compounds must, of course, be non-toxic and stable to rapid metabolic degradation. They may be organic or organometallic in nature .
  • non-peptide compounds are in principle no different from that of the peptides, as described above, but variations and limitations may be necessary according to the type of compound chosen.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Cette invention se rapporte à l'utilisation de composés, en particulier une classe de peptides, qui empêchent le déclenchement de la libération d'histamine par la dégranulation des mastocytes et qui, par voie de conséquence, inhibent la prolifération des carcinoomes. Cette invention se rapporte à l'utilisation d'un composé comprenant un premier atome ou groupe chargé négativement et un second atome au groupe chargé négativement, séparés par un groupe d'espacement qui, par sa conformation, permet de positionner ces atomes ou groupes chargés négativement de telle sorte qu'ils viennent neutraliser les résidus de lysine de la séquence d'acides aminés Lys Thr Lys aux positions 497-499 du domaine constant C⊂4 de l'IgE humaine, dans la fabrication d'un médicament pour le traitement des carcinomes, en particulier les adénocarcinomes mammaires. Cette invention se rapporte à l'utilisation d'un peptide représenté par la formule (I) (dans laquelle le côté gauche représente la terminaison N et le côté droit la terminaison C): R1m Xaa?1 Sp Xaa2 R2¿n (numéro d'identification de séquence: 1), où : R1 représente un résidu d'un acide aminé ou d'une séquence de deux acides aminés ou davantage qui peuvent être identiques ou différents; R2 représente un résidu d'un acide aminé ou d'une séquence de deux acides aminés ou davantage, qui peuvent être identiques ou différents; (mais, de préférence, tout résidu d'acides aminés de R1 ou R2 adjacent à un résidu Xaa n'est chargé ni positivement ni négativement); Xaa1 représente un résidu d'un acide aminé chargé négativement, de préférence Glu; Sp représente un résidu d'espacement, de préférence d'un acide aminé non chargé, de préférence Pro, ou d'un dipeptide non chargé, qui assure que l'espacement nécessaire pour les groupes chargés négativement des résidus Xaa soient suffisamment proches des résidus de lysine de la séquence d'acides aminés Lys Thr Lys aux positions 497-499 du domaine constant C⊂4 de l'IgE humaine pour les neutraliser; Xaa2 représente un résidu d'un acide aminé chargé négativement, de préférence Glu; et m et n sont égaux au nombre des acides aminés compris dans R1 et R2 respectivement et chacun des éléments m et n est séparément égal à 0 ou à un nombre entier compris entre 1 et 22, et la somme de m plus n est comprise entre 0 et 22; cette invention se rapportant en outre aux dérivés fonctionnels terminaux de ces composés, qui sont utilisés dans la fabrication d'un médicament pour le traitement des carcinomes, en particulier les adénocarcinomes mammaires.
PCT/GB1995/001892 1994-08-12 1995-08-10 Composes utilises dans le traitement des carcinomes WO1996005220A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU32266/95A AU3226695A (en) 1994-08-12 1995-08-10 Compounds for use in treatment of carcinomas

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9416316.9 1994-08-12
GB9416316A GB9416316D0 (en) 1994-08-12 1994-08-12 Compounds for use in treatment of carcinomas

Publications (1)

Publication Number Publication Date
WO1996005220A1 true WO1996005220A1 (fr) 1996-02-22

Family

ID=10759784

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1995/001892 WO1996005220A1 (fr) 1994-08-12 1995-08-10 Composes utilises dans le traitement des carcinomes

Country Status (3)

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AU (1) AU3226695A (fr)
GB (1) GB9416316D0 (fr)
WO (1) WO1996005220A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995010532A1 (fr) * 1993-10-11 1995-04-20 Peptide Therapeutics Limited Composes utilises dans les traitements anti-allergies

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995010532A1 (fr) * 1993-10-11 1995-04-20 Peptide Therapeutics Limited Composes utilises dans les traitements anti-allergies

Also Published As

Publication number Publication date
AU3226695A (en) 1996-03-07
GB9416316D0 (en) 1994-10-05

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