EP1189939A1 - Peptides modifies bh3 - Google Patents

Peptides modifies bh3

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Publication number
EP1189939A1
EP1189939A1 EP00943091A EP00943091A EP1189939A1 EP 1189939 A1 EP1189939 A1 EP 1189939A1 EP 00943091 A EP00943091 A EP 00943091A EP 00943091 A EP00943091 A EP 00943091A EP 1189939 A1 EP1189939 A1 EP 1189939A1
Authority
EP
European Patent Office
Prior art keywords
leu
ser
amino acid
asn
val
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00943091A
Other languages
German (de)
English (en)
Inventor
Barry A. Morgan
Gregoire Prevost
Thomas G. Cotter
Nicola Finnegan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ipsen Pharma SAS
Original Assignee
Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
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 Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS filed Critical Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
Publication of EP1189939A1 publication Critical patent/EP1189939A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4747—Apoptosis related proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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 is directed to a peptide of formula (I), as defined herein, or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising said peptide of formula (I), and the use thereof to restore apoptosis in human tumor cells.
  • the proliferation rate of a cell population reflects a balance between cell division, cell cycle arrest, differentiation, and programmed cell death or apoptosis (Rudin, CM. and Thompson, Annu. Rev. Med., 48:267-81 , 1997).
  • the regulation of these processes is central to development and tissue homeostasis, whereas dysregulation may lead to overt pathological outcomes, notably cancer and neurodegenerative disorders (Spengler, D., et al., EMBO J., 16: 2814-2825, 1997).
  • Apoptosis comprises an intrinsic cellular defense against tumorigenesis, which, when suppressed, may contribute to the development of malignancies (Reed, J.C., Cancer J. Sci. Am., 4 Suppl 1 :S8-14, 1998.
  • the Bcl-2 oncogene product functions as a potent suppressor of apoptosis under diverse conditions (Kroemer, G. (published erratum appears in Nat Med 1997 Aug; 3(8):934), Nat.Med., 3: 614-620, 1997).
  • Bcl-2 inhibits apoptosis induced by a wide variety of stimuli.
  • the Bcl-2 protein is found to be over-expressed in many types of human tumors. Protein-protein interaction between members of the Bcl-2 family of proteins seems to be a key event in the regulation of apoptosis .
  • the family of Bcl2-related proteins is constituted by survival proteins such as Bcl2, and Bcl-xL (Antonawich, F.J., et al., J. Cereb. Blood Flow Metab., 18: 882- 886, 1998), and death-promoting proteins such as Bad, Bak, Bax, Bip1 , Bik, Bcl-xS etc. (Boyd, J.M., et al., Oncogene, 11 : 1921-1928, 1995; Jurgensmeier, J.M., et al., Proc. Natl. Acad. Sci.
  • Bak was identified to promote cell death, and counteract the protection from apoptosis provided by Bcl-2. Moreover, enforced expression of Bak induces rapid and extensive apoptosis of serum- deprived fibroblasts (Chittenden, T., et al. EMBO J., 14: 5589-5596, 1995). Mutations in Bak that disrupt either type of interaction inhibit the ability of Bak to heterodimerize with Bcl-xL (Sattler, M., Science, 275: 983-986, 1997).
  • Bax antagonizes Bcl-2's death protecting function.
  • Bcl-2 can formhomodimers with itself and heterodimers with Bax and it has been shown that point mutations in Bcl-2 can abrogate Bax binding while leaving homodimerization intact (Diaz, J. L, et al., J. Biol. Chem., 272: 11350-11355, 1997).
  • the results from mutagenesis studies have led to the proposal that Bcl-2 has separate binding sites that are responsible for homodimer and heterodimer formation.
  • Results from yeast two-hybrid studies have also suggested that homodimerization and heterodimerization reflect distinct modes of interaction.
  • Bak One domain in Bak, termed BH-3, was identified to be both necessary and sufficient for cytotoxic activity and binding to Bcl-xL (Chittenden, T., et al., EMBO J., 14: 5589-5596, 1995). Sequences similar to this domain were identified in Bax and Bip1 , two other proteins that promote apoptosis and interact with Bcl-xL, and were likewise critical for their capacity to kill cells and bind Bcl-xL.
  • the BH3 domains of pro-apoptotic proteins are sufficient to trigger apoptosis accompanied by the release of cytochrome C from mitochondria and caspase activation.
  • the ability of synthetic peptides to reproduce the effect of pro- apoptotic BH3 domains suggests that such peptides may be useful in the diagnosis and treatment of proliferative disease, and may provide the basis for engineering reagents to control the initiation of apoptosis.
  • the present invention is directed to a peptide of formula (I) which disrupt the physical interaction between pro-apoptotic and anti-apoptotic proteins leading to induction of apoptosis in human tumoral prostate cells.
  • the present invention is directed to a compound of the formula (I):
  • a 1 is absent or an aliphatic amino acid
  • a 2 is absent or is selected from the group consisting of Gly, Ala, Ser, Thr and Asn;
  • a 3 and A 4 are each absent or are each a coded amino acid ;
  • a 5 is an aliphatic amino acid
  • a 6 is Ala or a basic amino acid
  • a 7 is selected from the group consisting of lie, Leu, Val, Ser, Thr, Lys and Arg;
  • a 8 is an aliphatic amino acid
  • a 9 is Gly
  • a 10 and A 11 are each independently Asp or Glu;
  • a 12 is an aliphatic amino acid lie, Leu Met and Val;
  • a 13 is Asp, Glu or Asn
  • a 14 and A 15 are each independently absent or selected from the group consisting of lie, Leu, Val, Met, Ser, Thr, Asn, Lys and Arg;
  • R 1 is (d-Cs) alkyl.
  • a preferred group of compounds of formula (I), are those compounds that have
  • a 1 is absent or lie, Leu, Met or Val;
  • a 2 is absent or is Gly, Ala, Ser, Thr and Asn;
  • a 5 is lie, Leu, Met or Val
  • a 8 is lie, Leu, Met and Val
  • a 9 is Gly
  • a 12 is lie, Leu Met and Val
  • a 13 is Asp, Glu or Asn, and the other variables of formula (I) are as defined above.
  • a preferred group of compounds of formula(l), are those compounds wherein A 6 is Ala, Lys or Arg and the other variables of formula (I) are as defined above.
  • Especially preferred compounds of formula (I) are Ac-Leu-Ser-Glu-Cys-Leu-Lys-Arg-lle-Gly-Asp-Glu-Leu-Asp-Ser-Asn-NH 2 , and Ac-Leu-Ser-Glu-Ser-Leu-Lys-Arg-lle-Gly-Asp-Glu-Leu-Asp-Ser-Asn-NH 2 .
  • a peptide of formula (I) can be synthesized by any standard solid phase peptide synthesis. See, e.g., Stewart, J.M., et al., Solid Phase Synthesis (Pierce Chemical Co., 2d ed. 1984).
  • the substituent R of a peptide of formula (I) can be attached to the free amine of the N-terminal amino acid by standard methods known in the art.
  • acyl groups may be attached by coupling the corresponding free acid of the acyl group, to the free amine of the N-terminal amino acid by mixing the completed resin with 3 molar equivalents of both the free acid and diisopropylcarbodiimide in methylene chloride for about one hour.
  • Peptides of the present invention can be and were synthesized on Rink Amide MBHA resin, (4-(2',4'-dimethoxyphenyl-Fmoc-aminomethyl)- phenoxyacetamido-norleucyl-MBHA resin), using a standard solid phase protocol for FMOC chemistry and cleaved from the resin with a TFA/Phenol/H 2 0/triisopropylsilane (83ml/5g/10ml/2ml) mixture.
  • Peptides were cyclized in CH 3 CN/H 2 0 (5ml/5ml) using EKATHIOXTM resin (EKAGEN Corporation, San Carlos, CA) and purified on C 18 silica (Rainin Instruments Co., Wobum, MA now Varian Analytical, Walnut Creek, CA), using acetonitrile/0.1 % trifluoroacetic acid buffers. Homogeneity was assessed by analytical HPLC and were determined to be >95% for each peptide. Peptides were characterized by HPLC and mass spectrometry.
  • Example 1 Ac-Leu-Ser-Glu-Cvs-Leu-Lvs-Arg-lle-Gly-Asp-Glu-Leu-Asp-Ser-Asn-
  • the peptides of this invention can be provided in the form of pharmaceutically acceptable salts.
  • such salts include, but are not limited to, those formed with organic acids (e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, methanesulfonic, toluenesulfonic, or pamoic acid), inorganic acids (e.g., hydrochloric acid, sulfuric acid, or phosphoric acid), and polymeric acids (e.g., tannic acid, carboxymethyl cellulose, polylactic, polyglycolic, or copolymers of poly lactic-g lycol ic acids).
  • organic acids e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, methanesulfonic, toluenesulfonic, or pamoic acid
  • inorganic acids e.g., hydrochloric acid, sulfuric acid
  • a typical method of making a salt of a peptide of the present invention is well known in the art and can be accomplished by standard methods of salt exchange. Accordingly, the TFA salt of a peptide of the present invention (the TFA salt results from the purification of the peptide by using preparative HPLC, eluting with TFA containing buffer solutions) can be converted into another salt, such as an acetate salt by dissolving the peptide in a small amount of 0.25 N acetic acid aqueous solution. The resulting solution is applied to a semi-prep HPLC column (Zorbax, 300 SB, C-8).
  • the column is eluted with (1) 0.1 N ammonium acetate aqueous solution for 0.5 hrs., (2) 0.25N acetic acid aqueous solution for 0.5 hrs. and (3) a linear gradient (20% to 100% of solution B over 30 min.) at a flow rate of 4 ml/min (solution A is 0.25N acetic acid aqueous solution; solution B is 0.25N acetic acid in acetonitrile/water, 80:20).
  • solution A is 0.25N acetic acid aqueous solution
  • solution B is 0.25N acetic acid in acetonitrile/water, 80:20.
  • the fractions containing the peptide are collected and lyophilized to dryness.
  • a peptide of formula (I) to induce apoptosis and mimic the effect of pro-apoptotic BH3 domains indicates that such peptides provide the basis for the development of assay procedures for the discovery of novel structures which initiate apoptosis in transformed cells.
  • a peptide of formula (I) can be used in a method for the biochemical and molecular characterization of tumor cells obtained from cancer patients. Such methods can help in the design of the best curative treatment for each patient. Examples of such methods, are a method for the analysis of relevant molecular determinants of tumor cell growth such as oncogenes and growth factor receptors, among others, and a method for the analysis of tumor cell apoptosis, such as p53 gene status and Bcl-2 family proteins, among others.
  • BcI2 family members
  • the activity of these proteins is linked to their status of binding with other members by BH3 domains.
  • Pro-apoptotic proteins such as Bax and Bak, bind to the anti-apoptotic Bcl-2 via these domains, leading to the inactivation of the normal ability of Bcl-2 to suppress apoptosis.
  • Bcl2 protein may be said to prevent apoptosis by neutralizing the pro-apoptotic members.
  • competitive dimerization between family members is thought to regulate the apoptosis rate.
  • the present invention provides a method of using a peptide of formula (I) to evaluate the levels of free Bcl2 or bound Bcl2 in tumor cells from biopsies. For this utility, it may be advantageous for the BH3 analogs to be coupled to a species which allows improved cell permeation.
  • BH3 analog radioactive, coupled to colorimetric system, coupled to fluorescence system
  • This methodology could assist in both diagnostic procedures, identification of treatment protocol, and in determination of prognosis, by identifying the potential for restoration of apoptosis.
  • Restoration of apoptosis in human tumoral cells should be a way to block tumorigenesis.
  • electroporation assisted delivery allowing the cell penetration of a peptide of formula (I) has been employed .
  • Cells were harvested during the exponential growth phase by trypsination and resuspended at a concentration of 0.625 10 6 cells/ ml of Phosphate buffered saline. A 0.8 ml aliquot was taken from the cell suspension and mixed with the compounds or the vehicle (DMSO), allowed to stand for 10 minutes and added to a disposable 0.4 cm electroporation cuvette (Bioraad). Electroporation was carried out in a Gene Pulser (Biorad) with cells exposed to one pulse. The capacitance of 25 ⁇ F and the voltage of 0.6kV were the preferred settings for electroporation.
  • the Bak/Bcl2 complex is detected in the prostatic cell line PC3. However, when cells were previously pretreated with Example 2 (with electroporation), the Bak/Bcl2 complex is not detectable. The results are a clear indication that a peptide of formula (I) prevents the formation of Bak/Bcl2 complex.
  • One of the downstream effects of apoptosis induction is the activation of the caspase family of proteases, transforming an inactive pro-caspase to an active caspase by internal proteolytic process. As shown in Table III, Example 2 did not induce apoptosis in the presence of caspase inhibitor z-VAD.fmk, which supports the mechanism that the apoptotic effect was via caspase activation.
  • a peptide of formula (I) of the instant application may be linked to or administered with a carrier which allows a peptide of formula (I) to cross the cell membrane.
  • a compound of the instant application can be linked to carriers such as biotin (Chen, L.L., et al., Anal. Biochem., 227: 168-175, 1995), Tat (Fawell, S., et al., Proc. Natl. Acad. Sci. U.S.A., 91: 664-668, 1994) penetratin (Derossi, D., et al., Trends Cell Biol., 8: 84-87, 1998), growth factors for receptor which are able to be internalized (e.g.
  • EGF-R EGF-R
  • Chitosan which is a high molecular weight cationic polysaccharide has been reported to enhance the absorption of peptides such as insulin across the nasal epithelium has also to be mentioned (Felt, O., et al., Drug Dev. Ind. Pharm., 24: 979-993, 1998).
  • a peptide of formula (I) can be tested for its pro-apoptotic according to the following method.
  • Material and methods Cell lines: The cell lines DU145 (HTB-81 ) and PC3 (CRL-1435) were established from human prostatic tumors and were issued from American Tumor Tissue Collection (Maryland, USA).
  • apoptosis levels were assessed by flow cytometry for up to 48 hours on a Becton Dickinson FACScan by propidium iodide (PI) (Sigma, Ireland) uptake and annexin V binding (Bender Medsystem, Ireland).
  • PI propidium iodide
  • annexin V binding Bender Medsystem, Ireland.
  • Control and treated cells were washed once with PBS by centrifugation at 400 x g, resuspended in HEPES buffer (10 mM HEPES-NaOH, pH 7.4, 150 mM NaCI, 5 mM KCI, 12 mM MgCI 2 and 1.8 mM CaCI 2 ), incubated with FITC-conjugated annexin V (Fluorescein iothiocyanate) (1 ⁇ g/ml) (Bender MedSystems, Ireland) and propidium iodide (10 ⁇ g/ml) (Sigma Ireland) for about 5 min at room temperature and immediately analyzed by flow cytometry to quantitate annexin V binding. A minimum of 10,000 events were collected for each sample.
  • HEPES buffer 10 mM HEPES-NaOH, pH 7.4, 150 mM NaCI, 5 mM KCI, 12 mM MgCI 2 and 1.8 mM CaCI 2
  • Bcl-2 For immunoprecipitation of Bcl-2, a monoclonal anti-Bcl-2 antibody (6 ⁇ g) coupled to agarose beads (Santa Cruz, Ireland) was added to 300 ⁇ g of protein from each sample, PBS was added to make the final volume up to 1 ml, mixed and incubated on ice for 90 min. Immunoprecipitates were collected by centrifugation at 14,000 x g for 5 min and washed three times with 1 ml of NP-40 lysis buffer.
  • a monoclonal anti-Bcl-2 antibody (6 ⁇ g) coupled to agarose beads (Santa Cruz, Ireland) was added to 300 ⁇ g of protein from each sample, PBS was added to make the final volume up to 1 ml, mixed and incubated on ice for 90 min. Immunoprecipitates were collected by centrifugation at 14,000 x g for 5 min and washed three times with 1 ml of NP-40 lysis buffer.
  • lysates were pre-cleared with 30 ⁇ l of goat anti-mouse IgG agarose (Sigma, Ireland) for about 30 min, which was removed by centrifugation at 14,000 x g for 10 mins.
  • Specific antibodies anti- Bak (2.5 ⁇ g/ml) (Calbiochem, San Diego, CA) or anti-Bax (8 ⁇ g/ml)) Immunotech, (Coulter, Miami, FL) were added to each sample and incubated on ice with shaking for 90 min. Immune complexes were captured by adding 80 ⁇ l of goat anti-mouse IgG agarose to each sample and left to shake at 4°C for 90 min. Samples were centrifuged at 14,000 x g for 15 min and washed three times with 1 ml each of cold lysis buffer.
  • Example 2 The effects of electroporation of Example 2 (50 ⁇ g/ml in DMSO) on cell PC3 survival levels of cells as assessed by Propidium uptake over time using flux cytometry. Table II
  • Example 2 The effects of electroporation of Example 2 (50 ⁇ g/ml in DMSO) on cell DU145 survival levels of cells as assessed by Propidium uptake over time using flux cytometry.
  • the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the peptides of formula (I) in association with a pharmaceutically acceptable carrier.
  • an effective dosage for the activities of this invention for example the treatment of acromegaly, is in the range of 0.01 to 200 mg/kg/day, preferably 0.5 to 100 mg/kg/day.
  • a peptide of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant
  • nasal, vaginal, rectal, sublingual or topical routes of administration can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch.
  • Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents. Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • non-aqueous solvents or vehicles examples include propylene giycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
  • Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as coca butter or a suppository wax.
  • compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
  • a compound of this invention can be administered in a sustained release composition such as those described in the following patents and patent applications.
  • U.S. Patent No. 5,672,659 teaches sustained release compositions comprising a bioactive agent and a polyester.
  • U.S. Patent No. 5,595,760 teaches sustained release compositions comprising a bioactive agent in a gelable form.
  • U.S. Patent No. 5,821 ,221 teaches polymeric sustained release compositions comprising a bioactive agent and chitosan.
  • U.S. Application No. 08/740,778 filed November 1 , 1996 teaches sustained release compositions comprising a bioactive agent and cyclodextrin.
  • the dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained.
  • the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. Generally, dosage levels of between 0.0001 to 100 mg/kg of body weight daily are administered to humans and other animals, e.g., mammals.
  • a preferred dosage range is 0.01 to 5.0 mg/kg of body weight daily which can be administered as a single dose or divided into multiple doses.
  • all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Also, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Toxicology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention se rapporte à un peptide représenté par la formule (I), définie dans la description associée, ou à un sel pharmaceutiquement acceptable de ce peptide, à des compositions pharmaceutiques comportant ledit peptide de formule (I) et à l'utilisation de ces compositions pour restaurer l'apoptose dans des cellules tumorales humaines. Le composé de formule (I) de la présente invention est R-A?1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-NHR1¿ ou un sel pharmaceutiquement acceptable de ce composé, où R est acyle (C¿1?-C5); A?1¿ est absent ou un acide aminé aliphatique; A2 est absent ou est sélectionné dans le groupe constitué par Gly, Ala, Ser, Thr et Asn; A3 et A4 sont chacun absents ou sont chacun un acide aminé codé; A5 est un acide aminé aliphatique; A6 est Ala ou un acide aminé basique; A7 est sélectionné dans le groupe constitué par Ile, Leu, Val, Ser, Thr, Lys et Arg; A8 est un acide aminé aliphatique; A9 est Gly; A?10 et A11¿ sont chacun indépendamment Asp ou Glu; A12 est un acide aminé aliphatique Ile, Leu Met et Val; A13 est Asp, Glu ou Asn; A?14 et A15¿ sont chacun indépendamment absent ou sélectionné dans le groupe constitué par Ile, Leu, Val, Met, Ser, Thr, Asn, Lys et Arg; et R1 est alkyle (C¿1?-C5).
EP00943091A 1999-06-25 2000-06-23 Peptides modifies bh3 Withdrawn EP1189939A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US14102799P 1999-06-25 1999-06-25
US141027P 1999-06-25
PCT/US2000/017283 WO2001000670A1 (fr) 1999-06-25 2000-06-23 Peptides modifies bh3

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EP (1) EP1189939A1 (fr)
JP (1) JP2003507471A (fr)
AU (1) AU5761200A (fr)
CA (1) CA2370099A1 (fr)
NO (1) NO20016188L (fr)
WO (1) WO2001000670A1 (fr)

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Publication number Priority date Publication date Assignee Title
KR100685345B1 (ko) 2004-03-27 2007-02-22 학교법인조선대학교 세포사 유도 펩타이드

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Publication number Priority date Publication date Assignee Title
US5656725A (en) * 1995-05-12 1997-08-12 Apoptosis Technology, Inc. Peptides and compositions which modulate apoptosis
WO1999016787A1 (fr) * 1997-09-26 1999-04-08 Washington University Agonistes de mort cellulaire

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0100670A1 *

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AU5761200A (en) 2001-01-31
JP2003507471A (ja) 2003-02-25
NO20016188L (no) 2002-02-21
NO20016188D0 (no) 2001-12-18
CA2370099A1 (fr) 2001-01-04
WO2001000670A1 (fr) 2001-01-04

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