EP1054899A2 - MOYEN DE TRAITEMENT DE PATHOLOGIES HUMAINES A PARTIR DE LA $g(b)-CATENINE, ET SON UTILISATION - Google Patents

MOYEN DE TRAITEMENT DE PATHOLOGIES HUMAINES A PARTIR DE LA $g(b)-CATENINE, ET SON UTILISATION

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Publication number
EP1054899A2
EP1054899A2 EP99913097A EP99913097A EP1054899A2 EP 1054899 A2 EP1054899 A2 EP 1054899A2 EP 99913097 A EP99913097 A EP 99913097A EP 99913097 A EP99913097 A EP 99913097A EP 1054899 A2 EP1054899 A2 EP 1054899A2
Authority
EP
European Patent Office
Prior art keywords
catenin
lef
peptides
tcf
interaction
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Withdrawn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
EP99913097A
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German (de)
English (en)
Inventor
Walter Birchmeier
Jens-Peter Von Kries
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.)
Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
Original Assignee
Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
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 Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft filed Critical Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
Publication of EP1054899A2 publication Critical patent/EP1054899A2/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Withdrawn legal-status Critical Current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
    • C07K14/4702—Regulators; Modulating activity
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • 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 invention relates to agents for the therapy of human diseases based on substances that interact with ß-catenin with transcription factors and
  • Affect tumor suppressor gene products are LEF-1- / TCF-4-
  • It also relates to a method for finding such substances and the use of the agent, preferably for the therapy of tumors such as colon cancer and
  • ⁇ -catenin is a cytoplasmic protein with various functions in the cell.
  • ß-catenin establishes the connection to the cytoskeleton (Hülsken, J. et al., E-cadherin and APC compete for the interaction with beta-catenin and the cytoskeleton. J-Cell-Biol. 127: 2061-9, 1994).
  • ß-catenin is a component of Wnt signal transduction that plays a major role in embryonic development.
  • the transcription factor LEF-1 was identified as an interaction partner of ⁇ -catenin in this signal cascade (Behrens, J.
  • a prerequisite for this ß-cateiiin-dependent signal transduction is the stabilization of the cytoplasmic pool of free, not cadherin-bound ß-catenin. This pool is negatively regulated by the glycogen synraetase kinase 3ß, by the tumor suppressor gene product APC and by Conductin / Axin.
  • APC mutations have been identified in the vast majority of colon cancers, while non-APC-deficient tumors have mutations in the ß-catenin gene.
  • the result of these mutations of APC or ß-catenin is the activation of signal transduction by the ß-catenin-LEF / TCF complex. It underlines the key role of ß-catenin in tumor development. Since APC mutations have been identified as an early event in the development of colon tumors, the activation of the ß-catenin-LEF / TCF complex is probably a key step in tumor development.
  • WO 98/42296 (Onyx Pharmaceuticals Inc. - Rubinfeld) relates to compositions and methods for the diagnosis and treatment of diseases which are triggered by ⁇ -catenin / transcription factor interactions.
  • the main claim relates to the isolated, stabilized ⁇ -catenin and its fragments, but such fragments have not been specified.
  • the aim of the invention described here is, firstly, to provide new agents for the treatment of carcinomas or aberrant tissue and organ development. It is based on the special task of influencing the interaction of ⁇ -catenin with LEF / TCF T ⁇ inscription factors as a prerequisite for the translocation and the activity of the complex in the cell nucleus. This modulation should be specific, ie it must not interfere with other interactions of ⁇ -catenin (eg with APC, Conductin or E-cadherin).
  • Another object of the invention is to develop ELISA methods for screening substance libraries to find molecules (inter alia peptides, organic compounds) which only influence one interaction of the ⁇ -catenin in a highly specific manner.
  • the binding domains of the LEF / TCF transcription factors for ⁇ -catenin were identified (Fig. 1). They are the starting point for the extraction of the peptides and similar molecules according to the invention. These peptides preferably consist of 10-20 amino acid long sequences from the N-terminal region of LEF-1 or TCF-4 (Fig. 2). The peptides are particularly preferred
  • peptides in which the acidic amino acids are arranged at a distance of 5 amino acids and flanked by hydrophobic and basic amino acids (Fig. 2).
  • these peptides can be used for tumor therapy, for which two basic ways are possible.
  • a direct use of the peptides for the treatment of tumors is generally out of the question because of their instability towards proteases and because of the lack of membrane permeability. Stabilization is achieved by coupling with a second peptide, for which the so-called Antennapedia peptide RQffilWFQNRRMEWEE is excellently suitable.
  • This peptide is able to transport peptides up to 100 amino acids long through cell membranes into the cytoplasm and the cell nucleus.
  • the coupled peptides can advantageously be used in tumor therapy.
  • the peptides according to the invention also serve as a basis for the design of substances which, through targeted modification, increase the stability and effectiveness in the cell (eptidomimetics). For example, this can be done by introducing reactive groups, exchanging amino acids or introducing non-hydrolyzable peptide-like bonds.
  • the stability of the molecules can also be increased by replacing the carbon skeleton of the peptides with synthetic carbon skeletons with the same arrangement of functional groups (non-peptidomimetics).
  • This molecular mimicry of the biological activity of the inhibitory peptides derived from the minimal binding domain of LEF-1 / TCF for ⁇ -catenin enables the production of more potent agents for tumor therapy.
  • ⁇ -catenin In a second step for realizing the invention, the regions of ⁇ -catenin were identified which are responsible for the specific bindings to LEF-I / TCF-4, APC (domains containing 20 and 15 amino acid repeats), conductin and E-cadherin . It was found that these regions partially overlap and relate to the A ⁇ nadillo domains 3-8 of ß-catenin (Fig. 5 and 6).
  • the key point of this step is that mutations of ⁇ -catenin have been generated which prevent specific interactions with individual partners. The following mutations are involved, based on the partial sequence of ß-catenin described in the Appendix (Tab. 1):
  • Wnt signal transduction and its components also play a role in the development and maintenance of tissues and organs, e.g. from certain regions of the brain, extremities, kidney and skin.
  • the tissue-specific elimination of the ß-catenin gene in the mouse shows that ß-catenin is important for the development of the skin and especially the hair.
  • the invention also extends to methods of promoting skin and hair development through increased expression of ⁇ -catenin (or of more stable ⁇ -catenin). This can be achieved, for example, by inhibiting the interaction with APC or Conductin.
  • inhibitors of the ⁇ -catenin / APC or the ⁇ -catenin / conductin interaction can be used in order to achieve increased ⁇ -catenin concentrations in cells and tissues.
  • Conductin which is a protein analogous to Axin, also requires the breakdown of ß-catenin.
  • Inhibitors of the ß-catenin / APC and ß-Catemn / Condin interaction can be used to intervene in organ development processes. For example, the hair development in humans could be demanded locally.
  • the 'yeast 2 hybrid system' was used to identify the minimal binding domain (Fig. 1).
  • the minimal binding domain could be limited to the N-terminal amino acids 11-27 of LEF-1, which corresponds to the amino acids 7-29 in TCF-4 (Fig.2).
  • the interaction of N-terminal LEF-1 fragments with ⁇ -catenin was determined on the basis of the activation of a lacZ reporter gene (see exemplary embodiment).
  • the amino acids essential for inhibition were identified by synthesis of mutant peptides (Fig.2).
  • a symmetrical arrangement of acidic amino acids (aspartic acid and glutamic acid) at a distance of 5 amino acids flanked by hydrophobic amino acids (leucine, isoleucine) and a basic amino acid (Lys) is essential for the function of the peptides.
  • the replacement of phenylalanine or lysine by alanine also cancels the inhibition by the peptide.
  • the importance of the acidic and aromatic amino acid residues was confirmed in the context of the entire LEF-1 molecule by a nuclear translocation test (Fig.4) of endogenous ß-catenin and by a transactivation test in mammalian cells.
  • the Armadillo region of ⁇ -catenin was developed by Huber et al. Crystallized in 1997 and characterized by X-ray crystal structure analysis. A basic pit was identified that could be responsible for the interaction with the acidic amino acids of LEF-1 (see above). Basic (Lys, Arg, His) and some aromatic (Trp) amino acids were therefore mutated in the armadillo repeat units 3-9 of ß-catenin (Fig.5). Care was taken to ensure that free amino acid residues from Heikes 3, which form the base of the pit, and some amino acid residues from one edge (helix 1) were mutated.
  • the mutant ß-catenins were tested to see whether they still interact with the interaction partners LEF / TCF, APC, Conductin and E-Cadherin (Table 2). With this method, critical amino acid residues of ß-catenin could be identified which are important for specific interactions (Fig. 5 and 6). As a result, it was possible to identify specific regions of ß-catenin for the individual interaction partners (Fig.6). These regions are important for the identification of molecules which specifically influence the interaction of ⁇ -catenin for LEF-1, APC, conductin or E-cadherin.
  • the finding that the binding domains of ⁇ -catenin partially overlap with LEF-1 / TCF, APC, conductin and E-cadherin is essential for the selection of new therapeutic agents.
  • the selection is e.g. substance libraries are tested to determine whether they specifically interact with ß-catenin with LEF-1 / TCF, with ß-catenin with APC (20 or 15 amino acid repeats), with ß-qitenin with conductin or with ß-
  • LEF-1 / TCF-4 The interaction with LEF-1 / TCF-4 is oncogenic in nature, i.e. potentially promotes cancer development, the interactions with APC, Conductin and E-Cadherin are potentially anti-oncogenic, i.e. they inhibit the development of cancer. Every new substance that intervenes in the Wnt signaling pathway must therefore be carefully tested for its specific effect.
  • the characterization of the binding domain of ⁇ -catenin presented here provides the basis for this. Substances that specifically reduce the ⁇ -catenin / LEF-1 / TCF-4 interaction are therefore potential anti-cancer therapeutics. Substances that inhibit interaction with APC, Conductin or E-Cadherin potentially promote the Wnt signaling pathway and can be used for increased tissue development, e.g. can be used to promote hair growth.
  • LEF-1 The interaction of partial domains of LEF-1 with ß-catenin was analyzed in the yeast 2-hybrid system by determining the ß-galactosidase activity according to the manufacturer (Clontech) (Fig.l).
  • the DNA coding for the N-terminal partial domains of LEF-1 was inserted into the cloning site of the vector BTM116 containing the Lex-A DNA binding domain and checked by sequencing.
  • the DNA fragments of LEF-1 were analyzed by polymerase chain reaction (PCR ) and incubation with restriction endonucleases.
  • the DNA encoding ⁇ -catenin was cloned into the vector pGAD424 (Clontech) for the activation domain of GAL-4 (Behrens et al. 1996).
  • the ß-galactosidase activities of independent experiments were averaged to compare the interaction of the hybrids.
  • the specificity of the interaction of the LEF-1 hybrids with ß-catenin was checked on the basis of the ß-galactosidase activity of yeasts which produced the LEF hybrids and the GAL-4 activation domain without ß-catenin (Fig. 1).
  • the expression of the LEF-1 hybrids was checked in the immunoblot with yeast cell Ly sows by antibodies (Clontech) against the Lex A domain of the hybrids. The same amounts of yeast were used to prepare the lysates after determining the optical density of the cultures.
  • Point mutations in the binding domain of LEF-1 for ⁇ -catenin were carried out by in vitro mutagenesis of the cDNA of LEF-1.
  • the mutagenesis was carried out using the "Transformer Site-Directed Mutagenesis Kit” from Clontech according to the manufacturer's instructions.
  • the following amino acids were substituted by alanine: Glu 14, Asp 19, Glu 20, Phe 24, Lys 25, Asp 26 and Glu 27.
  • the mutants were checked by sequencing and into the vector pCG-LEF-1 (Behrens et al. 1996) cloned. After transfection of MDCK cells with LEF-1 or its mutants, the translocation of endogenous ß-catenin into the cell nucleus was analyzed using immunocytological methods.
  • both proteins were produced recombinantly in bacteria with N-terminal histidine sequences and purified by nickel chromatography (Behrens et al. 1996).
  • the peptides were produced by the company Biosyntan with the PSSM-8 machine (Shimadzu, Japan) using the Fmoc / But strategy (E. Atherton and RC Sheppard. 1989 IRL Press, Oxford: “Solid phase peptide synthesis - a practical approach ").
  • Approximately 50 ng LEF-1 was adsorbed on the wells of ELISA plates for 90 minutes at room temperature.
  • PA2 was added for 10 minutes in a titer dilution of 1: 5000 in 3% skim milk powder in PBS. After washing the wells with PBS, the quantification by peroxidase-conjugated detection antibodies (1: 2500 in 3% skim milk powder in PBS, Dianova) and the conversion of o-phenylenediamine were determined by photometric measurement at 405 nm. The peptides were used in concentrations of 100 uM to 0.3 uM. To control the specificity of the inhibition of the interaction of LEF-1 / ß-catenin, ß-catenin was used in the
  • mutagenesis of ⁇ -catenin in the Armadillo repeats 3-8 was carried out using the "Mutagenese Kit” from Clontech according to the manufacturer's protocol and the mutants were checked by sequencing (Fig. 5). In all mutants, the original amino acid was substituted by alanine.
  • the cDNA coding for the amino acids Leu218-Leu781 from human ⁇ -catenin (A madillo repeat 3 to the C-terminal end of the protein) or its mutants was inserted into the fusion vector for the activation domain of Gal-4 (pGAD424 , Clontech).
  • the cDNA for the binding domains of the interaction partners was cloned into the LexA fusion vector BTM116.
  • the interaction of the Lex-A hybrids with ß-catenin and its mutants was quantified using the ß-galactosidase reporter activity in the yeast 2-hybrid system (protocol: "Matehmaker", Clontech) (Tab. 2 and Fig. 6).
  • the interaction of parts of the binding domain of LEF-1 with ß-catenin was analyzed using the ß-Gactosidase reporter activity in the yeast-2-hybrid system. Deletion of C-terminal amino acids from LEF-1 to Glu27 and N-terminal amino acids to GlylO leads to no loss of binding (11-27), while further deietions prevent the interaction (11-23, 17-34).
  • the minimal binding domain of LEF-1 for ß-catenin therefore consists of 17 amino acids (11-27) and has an acidic character.
  • the partial domain of LEF-1 from Met 21 to Val 56 shows no binding activity to ⁇ -catenin.
  • Synthetic peptides from the N-terminus of hTCF-4 with substitutions for the indicated amino acid residues were tested for their ability to inhibit the interaction of LEF-1 with ⁇ -catenin.
  • Substitution of the acidic amino acid residues of Asp 10, Aspl5 and Asp22 of TCF-4 by alanine leads to the cancellation of the inhibition by the corresponding peptides.
  • Substitution of Phe20 and Lys21 has the same effect.
  • An acidic, minimal binding domain of TCF-4 for ⁇ -catenin of 14 amino acids in length (Asp 10 to Glu23) was identified by deletion.
  • the synthetic peptide from the narrow binding domain of LEF-1 (10-34) inhibits the interaction of LEF-1 and ß-catenin in the ELISA. A reduction in complex formation to 50% is measured at a peptide concentration of 4 ⁇ M, while a peptide from LEF-1 with the amino acids Jle35-Val56 does not inhibit complex formation.
  • LEF-1 binding domain blocks the translocation of ⁇ -catenin into the cell nucleus.
  • the location of the mutations in relation to the structural context is shown.
  • the numbers above the amino acids in the sequence identify the mutants analyzed.
  • the mutants are color-coded with more than 70% reduction in the interaction for LEF-1 (red), APC (blue), Conductin (green) and E-Cadherin (yellow).
  • Amino acids highlighted in gray represent identical and chemically similar amino acids preserved in all repeats.
  • H aarrmm 4 4 ((226655-- -330066)) HQEGA MAVRLAGGLQKMVALLNKTNVKFLAITTDCLQI AY H arm 5 (307- -349) GNQESKLIILASGGPQALVNIMRTYTYEKLLWTTSRVLKVLSV
  • H is 260 3 53 37 - 1 -
  • the values indicate the percentage of the respective interaction with wild-type ⁇ -catenin. Interactions marked by - correspond to 60-100% of the wild-type interaction. The values were determined in yeast 2 hybrid assays.

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Abstract

LA β-catenine est une molécule centrale du chemin de signal Wnt. L'augmentation de la β-catenine dans la cellule entraîne la translocation dans le noyau de la cellule et l'interaction avec des facteurs de transcription de la famille LEF-1/TCF. Cela peut provoquer un cancer du colon et des mélanomes (chemin de signal oncogène). Mais la β-catenine interagit aussi avec les gènes suppresseurs de tumeurs APC, la conductine et la E-cadherine qui ont une action contraire sur la cellule (action anti-oncogène). L'invention concerne des peptides dérivés des facteurs de transcription du LEF-1-/TCF-4- et des molécules analogues dans le traitement de la tumeur, notamment pour le traitement de cancers du colon et de mélanomes. Ces peptides et molécules analogues influencent l'interaction entre la β-catenine et le LEF-1/TCF. Le domaine d'application de l'invention est l'industrie pharmaceutique et la médecine. L'invention concerne essentiellement les peptides, qui englobent des fractions des facteurs de transcription le LEF-1-/TCF-4-, et leurs variantes et mutants. Ils sont constitués, de préférence, de 10 à 40 acides aminés de la zone terminale N du LEFT-1 ou TCF-4. L'invention concerne également des peptides ou molécules analogues dérivés de la région armadillo de la β-catenine et identifiés comme domaines d'interaction avec le LEF-1/TCF, les APC, la conductine et la E-cadherine. Ces peptides ou molécules analogues peuvent également inhiber l'interaction entre la β-catenine et le LEF-1/TCF, ou augmenter la concentration de la β-catenine dans la cellule comme dans le cas des APC ou de la conductine. Ces dernières molécules peuvent être utilisées pour agir sur la formation des tissus et des organes, par exemple, pour favoriser la pousse des cheveux.
EP99913097A 1998-02-21 1999-02-22 MOYEN DE TRAITEMENT DE PATHOLOGIES HUMAINES A PARTIR DE LA $g(b)-CATENINE, ET SON UTILISATION Withdrawn EP1054899A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19807390 1998-02-21
DE19807390 1998-02-21
PCT/DE1999/000554 WO1999042481A2 (fr) 1998-02-21 1999-02-22 MOYEN DE TRAITEMENT DE PATHOLOGIES HUMAINES A PARTIR DE LA β-CATENINE, ET SON UTILISATION

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EP1054899A2 true EP1054899A2 (fr) 2000-11-29

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Country Status (6)

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US (1) US7067474B1 (fr)
EP (1) EP1054899A2 (fr)
JP (1) JP2002505255A (fr)
CA (1) CA2357015A1 (fr)
DE (1) DE19909251A1 (fr)
WO (1) WO1999042481A2 (fr)

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WO2001064949A2 (fr) * 2000-02-29 2001-09-07 Alcon Laboratories, Inc. Diagnostic et traitement du glaucome
ATE369144T1 (de) * 2000-03-31 2007-08-15 Gen Hospital Corp Verfahren zur steigerung des haarwuchses durch wnt polypeptid
CN1321647A (zh) * 2000-04-29 2001-11-14 上海博德基因开发有限公司 一种新的多肽——连环蛋白10和编码这种多肽的多核苷酸
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US20040247555A1 (en) * 2002-10-15 2004-12-09 Eli Sprecher Methods of and compositions for modulating hair growth via P-cadherin modulators
JP2007530016A (ja) 2004-02-27 2007-11-01 ザ ジェネラル ホスピタル コーポレーション 発毛のための方法および組成物
US9173871B2 (en) 2008-01-28 2015-11-03 New York University Oxazole and thiazole compounds as beta-catenin modulators and uses thereof
US8252823B2 (en) 2008-01-28 2012-08-28 New York University Oxazole and thiazole compounds as beta-catenin modulators and uses thereof
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CN110194787B (zh) * 2018-02-05 2022-05-17 中国医学科学院药物研究所 靶向抑制Wnt/β-catenin信号活性的多肽及其用途
CN114656549A (zh) * 2022-05-10 2022-06-24 南开大学 基于tip-1-多肽相互作用的新型分子胶水
KR102856525B1 (ko) * 2023-02-03 2025-09-09 한양대학교 에리카산학협력단 베타-카테닌 돌연변이체 또는 이를 발현하는 벡터를 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물

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DE19909251A1 (de) 1999-08-26
JP2002505255A (ja) 2002-02-19
US7067474B1 (en) 2006-06-27
WO1999042481A3 (fr) 2000-02-10
CA2357015A1 (fr) 1999-08-26
WO1999042481A2 (fr) 1999-08-26

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