[go: up one dir, main page]

WO2014170712A1 - Inhibiteurs de rac-1 ou inhibiteurs de pi3k pour la prévention d'un dysfonctionnement de la barrière intestinale - Google Patents

Inhibiteurs de rac-1 ou inhibiteurs de pi3k pour la prévention d'un dysfonctionnement de la barrière intestinale Download PDF

Info

Publication number
WO2014170712A1
WO2014170712A1 PCT/IB2013/001129 IB2013001129W WO2014170712A1 WO 2014170712 A1 WO2014170712 A1 WO 2014170712A1 IB 2013001129 W IB2013001129 W IB 2013001129W WO 2014170712 A1 WO2014170712 A1 WO 2014170712A1
Authority
WO
WIPO (PCT)
Prior art keywords
nod2
rac
autophagy
inhibitors
cells
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.)
Ceased
Application number
PCT/IB2013/001129
Other languages
English (en)
Inventor
Jean-Pierre Hugot
Frédérick BARREAU
Elodie THACHIL
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.)
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Diderot Paris 7
Original Assignee
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Diderot Paris 7
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 Institut National de la Sante et de la Recherche Medicale INSERM, Universite Paris Diderot Paris 7 filed Critical Institut National de la Sante et de la Recherche Medicale INSERM
Priority to PCT/IB2013/001129 priority Critical patent/WO2014170712A1/fr
Publication of WO2014170712A1 publication Critical patent/WO2014170712A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365Lactones
    • A61K31/366Lactones having six-membered rings, e.g. delta-lactones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/53751,4-Oxazines, e.g. morpholine
    • A61K31/53771,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/06Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • Inhibitors of gene expression for use in the present invention may be based on antisense oligonucleotide constructs.
  • Anti-sense oligonucleotides including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of the targeted mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of the targeted protein (i.e. PI3K or Rac-1), and thus activity, in a cell.
  • ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, which typically include the following sequences, GUA, GUU, and GUC. Once identified, short RNA sequences of between about 15 and 20 ribonucleotides corresponding to the region of the target gene containing the cleavage site can be evaluated for predicted structural features, such as secondary structure, that can render the oligonucleotide sequence unsuitable. The suitability of candidate targets can also be evaluated by testing their accessibility to hybridization with complementary oligonucleotides, using, e.g., ribonuclease protection assays.
  • PI3K activity in the panel of stably transfected Caco-2/TC7 cell lines was similarly increased after NS in all cell lines, suggesting an action of NOD2 downstream of PI3K.
  • NOD2 physically interacts with Rac-1.
  • Rac-1 In the control cell line, only a weak interaction was visible following NS. Although no interaction was observed in NOD2TM 1 overexpressing Caco-2/TC7 cells under basal conditions, NOD2/Racl strongly interacted after the induction of autophagy.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Transplantation (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés et des compositions pharmaceutiques pour un dysfonctionnement de la barrière intestinale en particulier chez les patients souffrant d'infections intestinales inflammatoires. En particulier, la présente invention porte sur un composé choisi parmi le groupe constitué d'inhibiteurs de Rac-1 ou d'inhibiteurs de PI3K devant être utilisés selon une méthode permettant d'empêcher le dysfonctionnement de la barrière intestinale chez un patient qui en a besoin.
PCT/IB2013/001129 2013-04-15 2013-04-15 Inhibiteurs de rac-1 ou inhibiteurs de pi3k pour la prévention d'un dysfonctionnement de la barrière intestinale Ceased WO2014170712A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IB2013/001129 WO2014170712A1 (fr) 2013-04-15 2013-04-15 Inhibiteurs de rac-1 ou inhibiteurs de pi3k pour la prévention d'un dysfonctionnement de la barrière intestinale

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2013/001129 WO2014170712A1 (fr) 2013-04-15 2013-04-15 Inhibiteurs de rac-1 ou inhibiteurs de pi3k pour la prévention d'un dysfonctionnement de la barrière intestinale

Publications (1)

Publication Number Publication Date
WO2014170712A1 true WO2014170712A1 (fr) 2014-10-23

Family

ID=48783283

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2013/001129 Ceased WO2014170712A1 (fr) 2013-04-15 2013-04-15 Inhibiteurs de rac-1 ou inhibiteurs de pi3k pour la prévention d'un dysfonctionnement de la barrière intestinale

Country Status (1)

Country Link
WO (1) WO2014170712A1 (fr)

Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032619A1 (fr) 1997-12-23 1999-07-01 The Carnegie Institution Of Washington Inhibition genetique par de l'arn double brin
US5981732A (en) 1998-12-04 1999-11-09 Isis Pharmaceuticals Inc. Antisense modulation of G-alpha-13 expression
US6046321A (en) 1999-04-09 2000-04-04 Isis Pharmaceuticals Inc. Antisense modulation of G-alpha-i1 expression
US6107091A (en) 1998-12-03 2000-08-22 Isis Pharmaceuticals Inc. Antisense inhibition of G-alpha-16 expression
WO2001036646A1 (fr) 1999-11-19 2001-05-25 Cancer Research Ventures Limited Inhibition d"expression genique a l"aide d"arn bicatenaire
WO2001068836A2 (fr) 2000-03-16 2001-09-20 Genetica, Inc. Procedes et compositions d'interference d'arn
US6365354B1 (en) 2000-07-31 2002-04-02 Isis Pharmaceuticals, Inc. Antisense modulation of lysophospholipase I expression
US6410323B1 (en) 1999-08-31 2002-06-25 Isis Pharmaceuticals, Inc. Antisense modulation of human Rho family gene expression
US6566135B1 (en) 2000-10-04 2003-05-20 Isis Pharmaceuticals, Inc. Antisense modulation of caspase 6 expression
US6566131B1 (en) 2000-10-04 2003-05-20 Isis Pharmaceuticals, Inc. Antisense modulation of Smad6 expression
US6573099B2 (en) 1998-03-20 2003-06-03 Benitec Australia, Ltd. Genetic constructs for delaying or repressing the expression of a target gene
WO2004076445A2 (fr) 2003-02-28 2004-09-10 Exonhit Therapeutics Sa Nouveaux composes et procedes de traitement de pathologies associees a la proliferation cellulaire, de retinopathies et de l'arthrite
WO2005051392A1 (fr) 2003-11-20 2005-06-09 Children's Hospital Medical Center Inhibiteurs de gtpase et procedes d'utilisation correspondants
WO2007016539A2 (fr) 2005-07-29 2007-02-08 Children's Hospital Medical Center Inhibiteurs de gtpase et methodes d'utilisation et structure cristalline de la gtpase rac-1
WO2007031878A2 (fr) 2005-07-27 2007-03-22 Exonhit Therapeutics Sa Methodes de traitement de troubles nerveux
WO2009007457A2 (fr) 2007-07-12 2009-01-15 Exonhit Therapeutics Sa Composés et procédés pour moduler les gtpases rho
US20090258837A1 (en) * 2005-07-22 2009-10-15 Giancarlo Naccari Analogous compounds of 6-thioguanosine triphosphate, their use in medical fields and processes for their preparation
EP2433636A1 (fr) 2010-09-27 2012-03-28 Medizinische Universität Wien Traitement de maladies malignes

Patent Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032619A1 (fr) 1997-12-23 1999-07-01 The Carnegie Institution Of Washington Inhibition genetique par de l'arn double brin
US6506559B1 (en) 1997-12-23 2003-01-14 Carnegie Institute Of Washington Genetic inhibition by double-stranded RNA
US6573099B2 (en) 1998-03-20 2003-06-03 Benitec Australia, Ltd. Genetic constructs for delaying or repressing the expression of a target gene
US6107091A (en) 1998-12-03 2000-08-22 Isis Pharmaceuticals Inc. Antisense inhibition of G-alpha-16 expression
US5981732A (en) 1998-12-04 1999-11-09 Isis Pharmaceuticals Inc. Antisense modulation of G-alpha-13 expression
US6046321A (en) 1999-04-09 2000-04-04 Isis Pharmaceuticals Inc. Antisense modulation of G-alpha-i1 expression
US6410323B1 (en) 1999-08-31 2002-06-25 Isis Pharmaceuticals, Inc. Antisense modulation of human Rho family gene expression
WO2001036646A1 (fr) 1999-11-19 2001-05-25 Cancer Research Ventures Limited Inhibition d"expression genique a l"aide d"arn bicatenaire
WO2001068836A2 (fr) 2000-03-16 2001-09-20 Genetica, Inc. Procedes et compositions d'interference d'arn
US6365354B1 (en) 2000-07-31 2002-04-02 Isis Pharmaceuticals, Inc. Antisense modulation of lysophospholipase I expression
US6566135B1 (en) 2000-10-04 2003-05-20 Isis Pharmaceuticals, Inc. Antisense modulation of caspase 6 expression
US6566131B1 (en) 2000-10-04 2003-05-20 Isis Pharmaceuticals, Inc. Antisense modulation of Smad6 expression
WO2004076445A2 (fr) 2003-02-28 2004-09-10 Exonhit Therapeutics Sa Nouveaux composes et procedes de traitement de pathologies associees a la proliferation cellulaire, de retinopathies et de l'arthrite
WO2005051392A1 (fr) 2003-11-20 2005-06-09 Children's Hospital Medical Center Inhibiteurs de gtpase et procedes d'utilisation correspondants
US20090258837A1 (en) * 2005-07-22 2009-10-15 Giancarlo Naccari Analogous compounds of 6-thioguanosine triphosphate, their use in medical fields and processes for their preparation
WO2007031878A2 (fr) 2005-07-27 2007-03-22 Exonhit Therapeutics Sa Methodes de traitement de troubles nerveux
WO2007016539A2 (fr) 2005-07-29 2007-02-08 Children's Hospital Medical Center Inhibiteurs de gtpase et methodes d'utilisation et structure cristalline de la gtpase rac-1
WO2009007457A2 (fr) 2007-07-12 2009-01-15 Exonhit Therapeutics Sa Composés et procédés pour moduler les gtpases rho
EP2433636A1 (fr) 2010-09-27 2012-03-28 Medizinische Universität Wien Traitement de maladies malignes

Non-Patent Citations (64)

* Cited by examiner, † Cited by third party
Title
APPENRODT, B. ET AL.: "Nucleotide-binding oligomerization domain containing 2 (NOD2) variants are genetic risk factors for death and spontaneous bacterial peritonitis in liver cirrhosis", HEPATOLOGY, vol. 51, pages 1327 - 1333
BARREAU, F. ET AL.: "CARD15/NOD2 is required for Peyer's patches homeostasis in mice", PLOS ONE, vol. 2, 2007, pages E523
BARREAU, F. ET AL.: "Nod2 regulates the host response towards microflora by modulating T cell function and epithelial permeability in mouse Peyer's patches", GUT, vol. 59, 2010, pages 207 - 217
BRENMOEHL, J ET AL.: "Genetic variants in the NOD2/CARD15 gene are associated with early mortality in sepsis patients", INTENSIVE CARE MED, vol. 33, 2007, pages 1541 - 1548
BRENMOEHL, J. ET AL.: "Genetic variants in the NOD2/CARD15 gene are associated with early mortality in sepsis patients", INTENSIVE CARE MED, vol. 33, 2007, pages 1541 - 1548
BRUEWER, M. ET AL.: "Interferon-gamma induces internalization of epithelial tight junction proteins via a macropinocytosis-like process", FASEB J, vol. 19, 2005, pages 923 - 933
BRUEWER, M.; HOPKINS, A.M.; HOBERT, M.E.; NUSRAT, A.; MADARA; J.L. RHOA: "Racl, and Cdc42 exert distinct effects on epithelial barrier via selective structural and biochemical modulation of junctional proteins and F-actin", AM JPHYSIOL CELL PHYSIOL, vol. 287, 2004, pages C327 - 335
BUHNER, S. ET AL.: "Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation?", GUT, vol. 55, 2006, pages 342 - 347
CADWELL, K ET AL.: "A key role for autophagy and the autophagy gene Atg1611 in mouse and human intestinal Paneth cells", NATURE, vol. 456, 2008, pages 259 - 263
CHANTRET, I ET AL.: "Differential expression of sucrase-isomaltase in clones isolated from early and late passages of the cell line Caco-2: evidence for glucose-dependent negative regulation", J CELL SCI, vol. 107, 1994, pages 213 - 225
CHEN, L.; ZHANG, B.; TOBOREK, M.: "Autophagy Is Involved In Nanoalumina- Induced Cerebrovascular Toxicity", NANOMEDICINE
CLAYBURGH, D.R.; SHEN, L.; TURNER, J.R.: "A porous defense: the leaky epithelial barrier in intestinal disease", LAB INVEST, vol. 84, 2004, pages 282 - 291
COONEY, R. ET AL.: "NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation", NAT MED, vol. 16, pages 90 - 97
CURRENT MEDICINAL CHEMISTRY, vol. 18, 2011, pages 2686 - 2714
DE KEYSER F; ELEWAUT D; DE VOS M; DE VLAM K; CUVELIER C; MIELANTS H; VEYS EM: "Bowel inflammation and the spondyloarthropathies", RHEUM DIS CLIN NORTH AM., vol. 24, no. 4, November 1998 (1998-11-01), pages 785 - 813
DHARMAWARDHANE, S. ET AL.: "Regulation of macropinocytosis by p21-activated kinase-1", MOL BIOL CELL, vol. 11, 2000, pages 3341 - 3352
DIEBEL, L.N.; LIBERATI, D.M.; BAYLOR, A.E., 3RD; BROWN, W.J.; DIGLIO, C.A.: "The pivotal role of tumor necrosis factor-alpha in signaling apoptosis in intestinal epithelial cells under shock conditions", J TRAUMA, vol. 58, 2005, pages 995 - 1001
D'INCA, R. ET AL.: "Increased intestinal permeability and NOD2 variants in familial and sporadic Crohn's disease", ALIMENT PHARMACOL THER, vol. 23, 2006, pages 1455 - 1461
EITEL, J. ET AL.: "Beta-PIX and Racl GTPase mediate trafficking and negative regulation of NOD2", J IMMUNOL, vol. 181, 2008, pages 2664 - 2671
FISHBEIN, T. ET AL.: "NOD2-expressing bone marrow-derived cells appear to regulate epithelial innate immunity of the transplanted human small intestine", GUT, vol. 57, 2008, pages 323 - 330
FRANKE, A. ET AL.: "Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci", NAT GENET, vol. 42, pages 1118 - 1125
FRIES, W. ET AL.: "Intestinal permeability and genetic determinants in patients, first-degree relatives, and controls in a high-incidence area of Crohn's disease in Southern Italy", AM J GASTROENTEROL, vol. 100, 2005, pages 2730 - 2736
GROSCHWITZ K R ET AL: "Intestinal barrier function: Molecular regulation and disease pathogenesis", JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 124, no. 1, 1 July 2009 (2009-07-01), pages 3 - 20, XP026217940, ISSN: 0091-6749, [retrieved on 20090626], DOI: 10.1016/J.JACI.2009.05.038 *
HAN, F. ET AL.: "Regulation of the ischemia-induced autophagy-lysosome processes by nitrosative stress in endothelial cells", J PINEAL RES, vol. 51, pages 124 - 135
HODIN, C.M. ET AL.: "Starvation compromises Paneth cells", AM JPATHOL, vol. 179, pages 2885 - 2893
HOLLANDER, D.: "Permeability in Crohn's disease: altered barrier functions in healthy relatives?", GASTROENTEROLOGY, vol. 104, 1993, pages 1848 - 1851
HOLLER, E. ET AL.: "Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation", BLOOD, vol. 104, 2004, pages 889 - 894
IRVINE, E.J.; MARSHALL, J.K.: "Increased intestinal permeability precedes the onset of Crohn's disease in a subject with familial risk", GASTROENTEROLOGY, vol. 119, 2000, pages 1740 - 1744
JUNG, C. ET AL.: "Yersinia pseudotuberculosis disrupts intestinal barrier integrity through hematopoietic TLR-2 signaling", J CLIN INVEST, vol. 122, pages 2239 - 2251
KATZ, K.D. ET AL.: "Intestinal permeability in patients with Crohn's disease and their healthy relatives", GASTROENTEROLOGY, vol. 97, 1989, pages 927 - 931
KLIONSKY, D.J.: "Autophagy: from phenomenology to molecular understanding in less than a decade", NAT REV MOL CELL BIOL, vol. 8, 2007, pages 931 - 937
KOIVUSALO, M.: "Amiloride inhibits macropinocytosis by lowering submembranous pH and preventing Rac1 and Cdc42 signaling", J CELL BIOL, vol. 188, pages 547 - 563
KONG DX; YAMORI T: "ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor identified using the JFCR39 drug discovery system", ACTA PHARMACOL SIN., vol. 31, no. 9, 23 August 2010 (2010-08-23), pages 1189 - 97
KRIEGLER: "A Laboratory Manual", 1990, W.H. FREEMAN C.O.
LECINE, P. ET AL.: "The NOD2-RICK complex signals from the plasma membrane", JBIOL CHEM, vol. 282, 2007, pages 15197 - 15207
LEGRAND-POELS, S ET AL.: "Modulation of Nod2-dependent NF-kappaB signaling by the actin cytoskeleton", J CELL SCI, vol. 120, 2007, pages 1299 - 1310
MACIAS-PEREZ IM; FLINN IW: "GS-1101: A Delta-Specific PI3K Inhibitor in Chronic Lymphocytic Leukemia", CURR HEMATOL MALIG REP., vol. 8, no. 1, March 2013 (2013-03-01), pages 22 - 7
MAEDA, S ET AL.: "Nod2 mutation in Crohn's disease potentiates NF-kappaB activity and IL-lbeta processing", SCIENCE, vol. 307, 2005, pages 734 - 738
MARCHIANDO, A.M. ET AL.: "Caveolin-1-dependent occludin endocytosis is required for TNF-induced tight junction regulation in vivo", J CELL BIOL, vol. 189, pages 111 - 126
MAY, G.R.; SUTHERLAND, L.R.; MEDDINGS, J.B.: "Is small intestinal permeability really increased in relatives of patients with Crohn's disease?", GASTROENTEROLOGY, vol. 104, 1993, pages 1627 - 1632
MEINZER, U. ET AL.: "Yersinia pseudotuberculosis effector YopJ subverts the Nod2/RICK/TAKl pathway and activates caspase-1 to induce intestinal barrier dysfunction", CELL HOST MICROBE, vol. 11, pages 337 - 351
MIZUSHIMA, N.; YAMAMOTO, A.; MATSUI, M.; YOSHIMORI, T.; OHSUMI, Y.: "In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker", MOL BIOL CELL, vol. 15, 2004, pages 1101 - 1111
MURRY: "Methods in Molecular Biology", vol. 7, 1991, HUMANA PRESS, INC.
NINGAPPA, M. ET AL.: "NOD2 gene polymorphism rs2066844 associates with need for combined liver-intestine transplantation in children with short-gut syndrome", AM J GASTROENTEROL, vol. 106, pages 157 - 165
PAPAKONSTANTI, E.A.; STOURNARAS, C.: "Association of PI-3 kinase with PAK1 leads to actin phosphorylation and cytoskeletal reorganization", MOL BIOL CELL, vol. 13, 2002, pages 2946 - 2962
PEETERS, M. ET AL.: "Clustering of increased small intestinal permeability in families with Crohn's disease", GASTROENTEROLOGY, vol. 113, 1997, pages 802 - 807
PODOLSKY, D.K.: "Inflammatory bowel disease", N ENGL J MED, vol. 347, 2002, pages 417 - 429
POPPE, D. ET AL.: "Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on Rac proteins", JLMMUNOL, vol. 176, 2006, pages 640 - 651
SALIM, S.Y.; SODERHOLM, J.D.: "Importance of disrupted intestinal barrier in inflammatory bowel diseases", INFLAMM BOWEL DIS, vol. 17, pages 362 - 381
SANBROOK ET AL.: "Molecular Cloning: A Laboratory Manual", 1989, COLD SPRING HARBOR LABORATORY PRESS
SHEN, L ET AL.: "Myosin light chain phosphorylation regulates barrier function by remodeling tight junction structure", J CELL SCI, vol. 119, 2006, pages 2095 - 2106
SODERHOLM, J.D. ET AL.: "Different intestinal permeability patterns in relatives and spouses of patients with Crohn's disease: an inherited defect in mucosal defence?", GUT, vol. 44, 1999, pages 96 - 100
SU, L. ET AL.: "Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis", GASTROENTEROLOGY, vol. 136, 2009, pages 551 - 563
TEAHON, K.; SMETHURST, P.; LEVI, A.J.; MENZIES, I.S.; BJARNASON, I.: "Intestinal permeability in patients with Crohn's disease and their first degree relatives", GUT, vol. 33, 1992, pages 320 - 323
THACHIL, E. ET AL.: "Abnormal Activation of Autophagy-Induced Crinophagy in Paneth Cells From Patients With Crohn's Disease", GASTROENTEROLOGY
TIEDE, I. ET AL.: "CD28-dependent Racl activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes", J CLIN INVEST, vol. 111, 2003, pages 1133 - 1145
TRAVASSOS, L.H.: "Nodl and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry", NAT IMMUNOL, vol. 11, pages 55 - 62
VERCAMMEN, D.; VANDENABEELE, P.; BEYAERT, R.; DECLERCQ, W.; FIERS, W.: "Tumour necrosis factor-induced necrosis versus anti-Fas-induced apoptosis in L929 cells", CYTOKINE, vol. 9, 1997, pages 801 - 808
VOJTEK, A. B.; COOPER, J. A., CELL, vol. 82, 1995, pages 527 - 529
WANG, F. ET AL.: "IFN-gamma-induced TNFR2 expression is required for TNF- dependent intestinal epithelial barrier dysfunction", GASTROENTEROLOGY, vol. 131, 2006, pages 1153 - 1163
WANG, F. ET AL.: "Interferon-gamma and tumor necrosis factor-alpha synergize to induce intestinal epithelial barrier dysfunction by up-regulating myosin light chain kinase expression", AM JPATHOL, vol. 166, 2005, pages 409 - 419
WYATT, J.; VOGELSANG, H.; HUBL, W.; WALDHOER, T.; LOCHS, H.: "Intestinal permeability and the prediction of relapse in Crohn's disease", LANCET, vol. 341, 1993, pages 1437 - 1439
YUAN GAO ET AL., PNAS, vol. 101, 18 May 2004 (2004-05-18), pages 7618 - 7623
ZEISSIG, S. ET AL.: "Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn's disease", GUT, vol. 56, 2007, pages 61 - 72

Similar Documents

Publication Publication Date Title
Reinwald et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Intracellular signaling pathways: tyrosine kinase and mTOR inhibitors)
Patel et al. Mechanisms of resistance to ABL kinase inhibition in CML and the development of next generation ABL kinase inhibitors
Ma et al. mTOR inhibition and kidney diseases
Zahoor et al. Hypoxia promotes IL-32 expression in myeloma cells, and high expression is associated with poor survival and bone loss
Mancini et al. RAD 001 (everolimus) prevents mTOR and Akt late re‐activation in response to imatinib in chronic myeloid leukemia
Song et al. Bis-N-norgliovictin, a small-molecule compound from marine fungus, inhibits LPS-induced inflammation in macrophages and improves survival in sepsis
Sakitani et al. Inhibition of autophagy exerts anti-colon cancer effects via apoptosis induced by p53 activation and ER stress
Gros et al. Pharmacological regulators of autophagy and their link with modulators of lupus disease
Kaeberlein mTOR inhibition: from aging to autism and beyond
Petrilli et al. A chemical biology approach identified PI3K as a potential therapeutic target for neurofibromatosis type 2
Chen et al. Novel Roles for Protein Kinase C;-dependent Signaling Pathways in Acute Hypoxic Stress-induced Autophagy
Yu et al. Phosphorylation of BECLIN-1 by BCR-ABL suppresses autophagy in chronic myeloid leukemia
JP7629228B2 (ja) Alk陰性癌および形質細胞媒介性疾患の治療のためのalk阻害剤
Zhu et al. IL‐7 suppresses macrophage autophagy and promotes liver pathology in Schistosoma japonicum‐infected mice
Fourneaux et al. Dual inhibition of the PI3K/AKT/mTOR pathway suppresses the growth of leiomyosarcomas but leads to ERK activation through mTORC2: biological and clinical implications
TW201526896A (zh) 藉二氫吡并吡組合療法的癌症治療方法
Ramis et al. A novel inhaled Syk inhibitor blocks mast cell degranulation and early asthmatic response
WO2019035866A1 (fr) Compositions et méthodes de traitement du complexe de la sclérose tubéreuse
Martínez-Borra et al. Autophagy and self-defense
WO2018038886A1 (fr) Procédés de traitement de tumeurs avec mutation de pten
Wang et al. KW2449 ameliorates collagen-induced arthritis by inhibiting RIPK1-dependent necroptosis
Xu et al. IL-4 activates ULK1/Atg9a/Rab9 in asthma, NLRP3 inflammasomes, and Golgi fragmentation by increasing autophagy flux and mitochondrial oxidative stress
Xu et al. Molecular mechanism and therapy application of necrosis during myocardial injury
Wißfeld et al. The immunosuppressive drug cyclosporin A has an immunostimulatory function in CD8+ T cells
Kandadi et al. Expression of Concern: Toll‐like receptor 4 knockout protects against anthrax lethal toxin‐induced cardiac contractile dysfunction: role of autophagy

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13736625

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13736625

Country of ref document: EP

Kind code of ref document: A1