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WO2008061673A2 - Découverte de médicaments contre le cancer - Google Patents

Découverte de médicaments contre le cancer Download PDF

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Publication number
WO2008061673A2
WO2008061673A2 PCT/EP2007/009910 EP2007009910W WO2008061673A2 WO 2008061673 A2 WO2008061673 A2 WO 2008061673A2 EP 2007009910 W EP2007009910 W EP 2007009910W WO 2008061673 A2 WO2008061673 A2 WO 2008061673A2
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Prior art keywords
gamma
secretase
aph
gene
cancer
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Ceased
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WO2008061673A3 (fr
Inventor
Karen Miriam Johanna Van Loo
Gerardus Johannes Maria Martens
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Synthon BV
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Synthon BV
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Publication of WO2008061673A3 publication Critical patent/WO2008061673A3/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)

Definitions

  • the present invention provides new methods and means for testing and screening compounds and materials, such as biologicals, drugs, and the like for efficacy in affecting, treating, or preventing cancer, in particular colon cancer and throat cancer.
  • Colorectal cancer is a major cause of death in the western world.
  • Current therapies involve surgical resection combined with chemotherapy (cytotoxic drugs and radiotherapy) .
  • the outcome of the disease is highly dependant on an early diagnosis. It is important that persons that are susceptible to the disease are monitored frequently to diagnose the disease in an early stadium. A method to diagnose the susceptibility of individuals to suffer cancer disease is therefore advantageous.
  • Notch/Wnt is a signalling pathway involved in self- renewal of the intestinal epithelium. Notch signaling is involved in maintenance of undifferentiated state of APC- mutant neoplastic cells.
  • the Wnt cascade is the driving force behind proliferative adenomas and adenocarcinomas of the intestine.
  • Notch signaling In most tissues, active Notch signaling is associated with an immature cell type. For terminal differentiation, this signaling has to be down-regulated. In some tissues, the opposite is required and Notch signaling is required for differentiation. In the latter tissues, loss of Notch signaling is associated with blocked differentiation and tumour progression. Over-expression of various proteins in the Notch signaling cascade has been found in renal cell carcinoma, prostate cancer, multiple myeloma, Hodgkins and anaplastic lymphomas. Accumulating data indicate that deregulated Notch activity is also involved in the genesis of other cancers (pancreatic, medulloblastoma, mucoepidermoid carcinoma) .
  • Aphl-b is a multipass transmembrane protein that interacts with presenilin and nicastrin as a functional component of the gamma-secretase complex.
  • the gamma-secretase complex is required for the intramembrane proteolysis of a number of membrane proteins, including the amyloid-beta precursor protein and Notch.
  • Goutte et al . (Proc Natl Acad Sci USA 99(2): 775-9 (2002)) concluded that Aphl and presenilins are required for cell surface localization of the Notch component Aph2 (nicastrin) .
  • SNP single-nucleotide polymorphism
  • Aph-lb is known as a component of the gamma-secretase complex. Subtle alterations in gamma-secretase subunit composition may lead to a variety of affected developmental signaling pathways and, consequently, aberrations in cell differentiation and growth.
  • SNP651 (T>G) in exon 6 of the Aph-lb gene showed a highly significant difference in the frequency of its genotype and allele between cancer patients and control groups.
  • the genotype frequency was found to be about 6-7% in the group of colon cancer patients against about 3% in controls (Table Ia) .
  • the genotype frequency for throat cancer was found to be 5.3% (Table Ib) .
  • the altered genotype leads to an altered gamma- secretase activity.
  • this mutation is the cause of a change in a normally conservative amino acid.
  • Gamma-secretase is the protease responsible for amyloid beta peptide release and is needed for Notch, N- Cadherin, and possibly other signaling pathways.
  • the protease complex consists of at least four subunits, i.e. presenilin, Aphl, Pen2, and Nicastrin. Two different genes encode Aph-la and Aph-lb in humans.
  • the present invention provides a new method for testing and screening compounds and materials, such as biologicals which can be proteins, peptides, antibodies or fragments thereof, liposomes, hormones, vectors, viral vectors, nucleic acid molecules, anti-sense RNA, si-RNA, drugs, and the like for efficacy in affecting, treating, or preventing cancer.
  • biologicals which can be proteins, peptides, antibodies or fragments thereof, liposomes, hormones, vectors, viral vectors, nucleic acid molecules, anti-sense RNA, si-RNA, drugs, and the like for efficacy in affecting, treating, or preventing cancer.
  • these compounds can be combined with any other compound used in the art for treating cancer, suitably formulated into a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, diluent and/or excipient.
  • the method comprises: a) providing a collection of compounds; b) contacting the compounds of the collection with a cell line or organism expressing gamma-secretase; c) measuring the gamma-secretase activity in the cell line or organism before and after the contact with the compound; and d) identifying the compounds in the collection that modulate the gamma-secretase activity of the cell line or organism.
  • the gamma-secretase that is expressed by the cell line or organism is a variant gamma-secretase, the activity of which is altered as compared to the gamma-secretase activity found in a human not carrying the SNP651 or carrying the wild-type Aph-lb gene.
  • the gamma-secretase activity is decreased as compared to the gamma-secretase activity found in a human not carrying the SNP651 or carrying the wild-type Aph-lb gene.
  • the phenylalanine at position 217 of the Aph-lb component of the gamma-secretase is replaced by an aliphatic amino acid, preferably leucine.
  • the method of the invention can also be performed with only one compound.
  • libraries of compounds are used.
  • Such a collection may include small molecules as well as macromolecules, such as nucleic acids or proteins.
  • Such compound libraries are known and commercially or otherwise available. In the future, other compound libraries will be developed. It is not an undue burden for the skilled person to screen such existing and new libraries and identify the compounds that have an effect on gamma- secretase activity.
  • the invention further relates to the compounds identified by the method, to compositions comprising one or more of such compounds together with an acceptable carrier and to pharmaceutical compositions or formulations comprising the composition.
  • the invention relates to any therapeutical or prophylactic use of compounds identified by the method, and in particular for the treatment or prophylaxis of cancer, in particular colon cancer or throat cancer.
  • the invention further provides for the use of a cell line that produces a human gamma-secretase in the method.
  • the gamma-secretase that is produced is a variant gamma- secretase, the activity of which is altered as compared to the gamma-secretase activity found in a human not carrying the SNP651 or carrying the wild-type Aph-lb gene.
  • the gamma-secretase activity is decreased as compared to the gamma-secretase activity found in a human not carrying the
  • the variant gamma-secretase is a gamma-secretase wherein the phenylalanine at position 217 of the Aph-lb component of the gamma-secretase is replaced by a leucine.
  • the cell line is constructed such that the Aph-lb component of the gamma- secretase is expressed from a Aph-lb gene harboring the SNP651 polymorphism.
  • the Aph-lb component of the gamma-secretase is expressed from a nucleic acid molecule comprising a variant of the human Aph-lb gene as depicted in Fig. 1 (SEQ ID NO:1) that causes the amino acid residue in position 217 of the encoded gamma-secretase component Aph-lb to be an aliphatic amino acid, in particular a leucine.
  • the variant Aph-lb gene has the nucleotide sequence as depicted in any one of the Figs. 2A-F (SEQ ID NOS:3-8), or a fragment thereof that comprises the codon encoding amino acid residue 217 of the encoded gamma- secretase component Aph-lb.
  • the variant Aph-lb gene may also have a nucleotide sequence encoding a polypeptide having the amino acid sequence as depicted in Fig. 4 (SEQ ID NO: 9) .
  • the variant Aph-lb gene hybridizes under high stringency conditions to a nucleotide sequence selected from the group consisting of the sequences as shown in any one of the Figs. 2A-F (SEQ ID NOS: 2-7) and the complement of the sequence as shown in any one of the Figs. 2A-F (SEQ ID NOS:2-7), with the proviso that the nucleic acid has a codon selected from TTA, TTG, CTT, CTC, CTA, CTG in the position encoding the amino acid residue in position 217 of the encoded gamma-secretase component Aph-lb.
  • the skilled person knows how to define "high stringency" conditions " for the different hybridisation techniques that are generally available.
  • the invention relates to the use of the cell line for identification of compounds that alter the gamma-secretase activity.
  • the cell line is either a transgenic cell line or a cell line derived from an individual that has the polymorphism.
  • results of the method of the invention can further be used in combination with the outcome of a diagnostic test determining the presence of SNP651.
  • SNP651 in an individual is indicative for susceptibility to develop cancer.
  • This presence of SNP651 defines a novel subgroup in the group of patients suffering from cancer and thereby, as a logical consequence, at least one causative factor responsible for development of the disease in this subgroup.
  • Specific targeting of this factor using the compounds according to the present invention offers the possibility to provide to this group of patients an improved, possibly additional, treatment protocol specifically designed to target the causative factor.
  • the invention can thus be used in combination with a method of diagnosing the susceptibility of a individual to develop cancer, comprising screening for the presence of SNP651 (SEQ ID NO: 10) in the gene encoding the human gamma- secretase component Aph-lb, which SNP651 is more frequently present in a population of individuals suffering from or susceptible to develop cancer than in the general population, and wherein the presence of SNP651 is indicative of the existence of cancer or susceptibility to develop cancer.
  • SNP651 SEQ ID NO: 10
  • the SNP651 is "more frequently present" when there is a significant increase in its occurrence as compared to the normal population.
  • the normal population and the patient are Caucasian.
  • SNP651 is a single nucleotide polymorphism in which the T in position 651 of the coding part of the gene (wherein the start codon ATG represent positions 1-3) is changed into G.
  • cancer is used to indicate any form of cancer.
  • the general term is used herein also the more specific colon cancer and throat cancer are intended. Every disclosure herein that mentions cancer in general is intended to be also a specific disclosure in relation to colon cancer and throat cancer.
  • Diagnosis of a susceptibility to develop cancer is thus made by detecting the SNP651 polymorphism in the Aph-lb gene.
  • the polymorphism is the change of one nucleotide, resulting in a change in the encoded amino acid.
  • hybridization methods such as Southern analysis, Northern analysis, or in situ hybridizations are used. These techniques are well known in the art and are for example disclosed in Current Protocols in Molecular Biology, Ausubel, F. et al., eds . , John Wiley & Sons, including all supplements .
  • test sample of genomic DNA, RNA, or cDNA
  • the test sample can be from any source which contains genomic DNA, such as a blood sample, sample of amniotic fluid, sample of cerebrospinal fluid, or tissue sample from skin, muscle, buccal or conjunctival mucosa, placenta, gastrointestinal tract a or other organs.
  • a test sample of DNA from fetal cells or tissue can be obtained by appropriate methods, such as by amniocentesis or chorionic villus sampling.
  • nucleic acid probe can be a DNA probe or an RNA probe; the nucleic acid probe contains the SNP651 polymorphism in Aph-lb.
  • the probe can be any of the nucleic acid molecules described above (e.g., the gene, a fragment, a vector comprising the gene, a probe or primer, etc . )
  • a hybridization sample is formed by contacting the test sample containing the Aph-lb gene, with at least one nucleic acid probe.
  • a preferred probe for detecting mRNA or genomic DNA is a labeled nucleic acid probe capable of hybridizing to mRNA or genomic DNA sequences described herein.
  • the nucleic acid probe can be, for example, a full-length nucleic acid molecule, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to appropriate mRNA or genomic DNA.
  • the nucleic acid probe can be all or a portion of the sequence shown in Figs.
  • Suitable probes for use in the diagnostic assays comprise a nucleotide that is complementary to position 651 of the Aph-lb gene or variant thereof.
  • the hybridization sample is maintained under conditions, which are sufficient to allow specific hybridization of the nucleic acid probe to the Aph-lb gene.
  • Specific hybridization indicates exact hybridization (e.g., with no mismatches). Specific hybridization can be performed under high stringency conditions or moderate stringency conditions. In a particularly preferred embodiment, the hybridization conditions for specific hybridization are high stringency.
  • Specific hybridization if present, is then detected using standard methods. If specific hybridization occurs between the nucleic acid probe and the Aph-lb gene in the test sample, then the Aph-lb gene has the polymorphism that is present in the nucleic acid probe. Specific hybridization of the nucleic acid probe is indicative of a polymorphism in the Aph-lb gene, and is therefore diagnostic for a susceptibility to develop cancer.
  • RNA from the individual is indicative of the SNP651 polymorphism in the Aph-lb gene, and is therefore diagnostic for a susceptibility to develop cancer.
  • a peptide nucleic acid (PNA) probe can be used instead of a nucleic acid probe in the hybridization methods described above.
  • PNA is a DNA mimic having a peptide- like, inorganic backbone, such as N- (2-aminoethyl) glycine units, with an organic base (A, G, C, T or U) attached to the glycine nitrogen via a methylene carbonyl linker (see, for example, Nielsen, P. E. et al . , Bioconjugate Chemistry, 1994, 5, American Chemical Society, p.
  • the PNA probe can be designed to specifically hybridize to the Aph-lb gene having the SNP651 polymorphism associated with a susceptibility to develop cancer. Hybridization of such PNA probe to the Aph-lb gene is diagnostic for a susceptibility to develop cancer.
  • Sequence analysis can also be used to detect the SNP651 polymorphism in the Aph-lb gene.
  • a test sample of DNA or RNA is obtained from the test individual. PCR or other appropriate methods can be used to amplify the gene, and/or its flanking sequences, if desired.
  • the sequence of the Aph- lb gene, or a fragment of the gene, or cDNA, or fragment of the cDNA, or mRNA, or fragment of the mRNA is determined, using standard methods.
  • the sequence of the gene, gene fragment, cDNA, cDNA fragment, mRNA, or mRNA fragment is compared with the known nucleic acid sequence of the gene, cDNA (e.g., Fig.
  • Allele-specific oligonucleotides can also be used to detect the presence of the SNP651 polymorphism in Aph-lb, through the use of dot-blot hybridization of amplified oligonucleotides with allele-specific oligonucleotide (ASO) probes (see, for example, Saiki, R. et al., (1986), Nature (London) 324:163-166).
  • ASO allele-specific oligonucleotide
  • an “allele-specific oligonucleotide” (also referred to herein as an “allele-specific oligonucleotide probe”) is an oligonucleotide of approximately 10-50 base pairs, preferably approximately 15- 30 base pairs, that specifically hybridizes to Aph-lb, and that contains a polymorphism associated with a susceptibility to develop cancer.
  • An allele-specific oligonucleotide probe that is specific for the SNP651 polymorphism in Aph-lb can be prepared, using standard methods (see Current Protocols in Molecular Biology, supra) .
  • a test sample of DNA is obtained from the individual.
  • PCR can be used to amplify all or a fragment of Aph-lb, and its flanking sequences.
  • the DNA containing the amplified Aph-lb (or fragment of the gene) is dot-blotted, using standard methods (see Current Protocols in Molecular Biology, supra), and the blot is contacted with the oligonucleotide probe.
  • the presence of specific hybridization of the probe to the amplified Aph-lb is then detected.
  • Specific hybridization of an allele-specific oligonucleotide probe to DNA from the individual is indicative of the SNP651 polymorphism in Aph-lb, and is therefore indicative of a susceptibility to develop cancer.
  • arrays of oligonucleotide probes that are complementary to target nucleic acid sequence segments from an individual can be used to identify the
  • an oligonucleotide array can be used. Oligonucleotide arrays typically comprise a plurality of different oligonucleotide probes that are coupled to a surface of a substrate in different known locations. One such oligonucleotide probe could be used to detect the presence of SNP651 in the target nucleic acid sequence segments from an individual. These oligonucleotide arrays, also described as "GenechipsTM, " have been generally described in the art, for example, U.S. Pat. No. 5,143,854 and PCT patent publication Nos. WO 90/15070 and 92/10092.
  • arrays can generally be produced using mechanical synthesis methods or light directed synthesis methods which incorporate a combination of photolithographic methods and solid phase oligonucleotide synthesis methods. See Fodor et al., Science, 251:767-777 (1991), Pirrung et al., U.S. Pat. No. 5,143,854 (see also PCT Application No. WO 90/15070) and Fodor et al., PCT Publication No. WO 92/10092 and U.S. Pat. No. 5,424,186, the entire teachings of each of which are incorporated by reference herein. Techniques for the synthesis of these arrays using mechanical synthesis methods are described in, e.g., U.S. Pat. No.
  • a nucleic acid of interest is hybridized with the array and scanned for polymorphisms.
  • Hybridization and scanning are generally carried out by methods described in, e.g. Published PCT Application Nos. WO 92/10092 and WO 95/11995, and U.S. Pat. No. 5,424,186, the entire teachings of which are incorporated by reference herein.
  • a target nucleic acid sequence which includes one or more previously identified polymorphic markers is amplified by well known amplification techniques, e.g., PCR.
  • Asymmetric PCR techniques may also be used.
  • Amplified target generally incorporating a label, is then hybridized with the array under appropriate conditions.
  • the array is scanned to determine the position on the array to which the target sequence hybridizes.
  • the hybridization data obtained from the scan is typically in the form of fluorescence intensities as a function of location on the array.
  • nucleic acid analysis can be used to detect the SNP651 polymorphism in Aph-lb.
  • Representative methods include direct manual sequencing (Church and Gilbert, (1988), Proc. Natl. Acad. Sci . USA 81:19911995; Sanger, F. et al. (1977) Proc. Natl. Acad. Sci. 74:5463-5467; Beavis et al. U.S. Pat. No. 5,288,644); automated fluorescent sequencing; single-stranded conformation polymorphism assays (SSCP) ; clamped denaturing gel electrophoresis (CDGE) ; denaturing gradient gel electrophoresis (DGGE) (Sheffield, V. C. et al.
  • the screening for the presence of SNP651 (SEQ ID NO: 1) in the gene encoding the human gamma-secretase component Aph-lb comprises the steps of: a) provision of nucleic acid from the individual to be tested; b) amplification of part of the nucleic acid of the individual to be tested with a primer comprising a contiguous nucleotide sequence, which is at least partially complementary to a part of the nucleotide sequence of said Aph-lb nucleic acid and which is capable of acting as a primer for said Aph-lb nucleic acid when maintained under conditions for primer extension; c) determining whether the amplification product is formed.
  • This embodiment is particularly advantageous when the primer is complementary to a stretch of nucleic acid located immediately upstream from the position of SNP651, and ends with an A or a C.
  • the primer with the 3 1 A (A- primer) will result in primer extension, whereas the primer with the C at the end (C-primer) will not be extended.
  • the PCR reaction on the nucleic acid sample of an individual having T/T at position 651 will not produce an amplification product with the C-primer but will result in an amplification product with the A-primer.
  • An individual having the SNP651 mutation at both alleles will produce a product with the C-primer but not with the A- primer.
  • the sample of a heterozygous individual will show a product with both primers.
  • two PCR' s with the two primers has the additional advantage of obtaining information about the homozygosity or heterozygosity of the individual, one PCR with one primer will also give the indication whether or not the individual has the genetic risk factor.
  • any other amplification technique such as NASBA or LCR, can be used.
  • Figures Figure 1 shows the 905 bp cDNA sequence of the known human Aph-lb gene (accession AL136671 from GenBank) encoding the variant component Aph-lb of the human gamma-secretase gene as identified according to the invention.
  • SNP651 is the nucleotide at position 651 of the coding sequence in which the ATG corresponds to positions 1-3.
  • Figures 2A-F show examples of variant Aph-lb genes.
  • Figure 3 shows the known amino acid sequence of the human Aph-lb component of ⁇ -secretase as found in the UniProtKB/Swiss-Prot at entry Q8WW43. The length is 257 amino acids, the molecular weight is 28460 Da.
  • the amino acid in position 217 in this figure will always be designated as "the amino acid residue in position 217" thus referring to the protein that naturally occurs in humans, even when the actual position of that amino acid in an amino acid sequence is not position 217.
  • Figure 4 shows the amino acid sequence of an example of a variant Aph-lb protein.
  • Fig. 1 SEQ ID N0:l known Aph-lb gene
  • Fig. 2A SEQ ID NO: 2 novel Aph-lb variant
  • Fig. 2B SEQ ID NO: 3 novel Aph-lb variant
  • Fig. 2E SEQ ID NO: 6 novel Aph-lb variant
  • Fig. 2F SEQ ID NO: 7 novel Aph-lb variant
  • a cell line expressing a variant gamma-secretase was prepared transforming the cells with the Aph-lb gene as depicted in Fig. 2A. Transformed clones were identified by means of markers. Insertion of the correct gene was determined by means of PCR with the following primers: forward primer: 5'- AATAAACCTGGCGTCAGCATTG -3 1 reversed primer: 5'- AGTCGGCTTTACACTGTCCCA -3 1 .
  • One of the transformed clones harbouring the gene of Fig. 2A was selected for the production of a cell line Aph- lb/T>G.
  • the basal level of the gamma-secretase of cell line Aph-lb/T>G was determined by measuring the levels of cleavage products of various gamma-secretase substrates by Western blot analysis using antibodies directed against the C- terminal regions of the substrates.
  • the proteolytic processing of a gamma-secretase substrate starts with shedding of its extracellular domain, leaving a C- terminal fragment (CTF) that is subsequently cleaved by gamma-secretase to its ICD.
  • CTF C- terminal fragment
  • One of the best known substrates of gamma-secretase is the Alzheimer's disease-linked APP protein.
  • APP is part of the APP superfamily that in mammals includes the two APP-like proteins APLPl and APLP2.
  • APLPl the two APP-like proteins
  • APLP2 the two APP-like proteins
  • NRG2 the gamma-secretase cleavage activity toward p75, ErbB4, and NRG2 was determined.
  • CTFs direct gamma- secretase substrates
  • the cell line was subsequently contacted with a collection of chemical compounds and the gamma-secretase activity again determined. Compounds that were capable of increasing the gamma-secretase activity were selected as leads.

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Abstract

La présente invention concerne un procédé permettant d'identifier des composés qui modifient l'activité gamma-secrétase. Le procédé selon l'invention consiste : à fournir une collection de composés; à mettre les composés de la collection en contact avec une lignée cellulaire ou un organisme exprimant la gamma-secrétase; à mesurer l'activité gamma-secrétase de la lignée cellulaire ou de l'organisme avant et après la mise en contact avec les composés; et à identifier les composés de la collection qui modulent l'activité gamma-secrétase de la lignée cellulaire ou de l'organisme comme étant des éléments de départ pour l'élaboration de composés destinés à traiter le cancer. L'invention se rapporte également au composé ainsi identifié et à son utilisation à des fins thérapeutiques.
PCT/EP2007/009910 2006-11-24 2007-11-08 Découverte de médicaments contre le cancer Ceased WO2008061673A2 (fr)

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EP1596878A4 (fr) * 2003-02-18 2008-05-28 Roskamp Res Llc Proprietes anti-angiogeniques et antitumorales des inhibiteurs de beta-secretase et de gamma-secretase
EP1481987A1 (fr) * 2003-05-26 2004-12-01 Aventis Pharma Deutschland GmbH Méthodes de criblage d'inhibiteurs de la gamma-sécrétase
ATE535614T1 (de) * 2003-12-30 2011-12-15 Kowa Co Screening-verfahren fuer gamma-sekretase- inhibitoren
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