WO2001034201A2 - Methodes de detection d'agents utiles pour inhiber la neurofibromatose de type 1 (nf1) - Google Patents

Methodes de detection d'agents utiles pour inhiber la neurofibromatose de type 1 (nf1) Download PDF

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Publication number
WO2001034201A2
WO2001034201A2 PCT/US2000/030924 US0030924W WO0134201A2 WO 2001034201 A2 WO2001034201 A2 WO 2001034201A2 US 0030924 W US0030924 W US 0030924W WO 0134201 A2 WO0134201 A2 WO 0134201A2
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Prior art keywords
nfl
cells
kinase
ras
scf
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PCT/US2000/030924
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English (en)
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WO2001034201A3 (fr
WO2001034201A9 (fr
Inventor
Wade D. Clapp
David A. Ingram
Mark Steven Marshall
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Advanced Research And Technology Institute, Inc.
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Application filed by Advanced Research And Technology Institute, Inc. filed Critical Advanced Research And Technology Institute, Inc.
Priority to EP00975626A priority Critical patent/EP1227846A2/fr
Priority to AU13647/01A priority patent/AU1364701A/en
Priority to CA002388343A priority patent/CA2388343A1/fr
Priority to JP2001536198A priority patent/JP2003513939A/ja
Publication of WO2001034201A2 publication Critical patent/WO2001034201A2/fr
Publication of WO2001034201A3 publication Critical patent/WO2001034201A3/fr
Publication of WO2001034201A9 publication Critical patent/WO2001034201A9/fr

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    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic 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
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4703—Regulators; Modulating 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
    • G01N2500/10—Screening for compounds of potential therapeutic value involving cells

Definitions

  • the invention provides a therapeutic method for treating the clinical manifestations of NFl in a mammal.
  • the method comprises administering to a mammal in need to such treatment an effective amount of an agent that directly or indirectly inhibits the activity at least one protein selected from the group consisting of Raf, MEK, extracellular signal regulated kinase 1 (ERKl), extracellular signal regulated kinase 2 (ERK2), phosphatidylinositol triphosphate kinase (PI3K), p21 activated kinase 2 (PAK2), p21 activated kinase 3 (PAK3), Rac, CDC42, p21 activated kinase 1 (PAKl), protein kinase B (PKB), Akt, and c-jun N-terminal kinase (JNK), e.g., so as to inhibit abnormal cellular growth or pruritus due to NF-1.
  • an agent that directly or indirectly inhibits the activity at least
  • Asterisk indicates P ⁇ 0.05 for comparison of Nfl +/-; ⁇ '/ F 41 to +/+; r ⁇ W 41 and Nfl +/-; +/+ to +/+; +/+ cells by Student's paired t-test.
  • Figure 8 Schematic representation of c-kit mediated Ras-Raf-ERK and PI-3-kinase signaling pathways and potential cross talk between them.
  • Neurofibromas are composed of Schwann cells, endothelial cells, fibroblasts, and mast cells (reviewed, Riccardi, 1992). Though numerous investigators have examined different aspects of neurofibroma biology (Stark et al., 1995; Sawada et al., 1996; Colman et al., 1995; Badache et al., 1998; Hirota et al., 1993; Rosenbaum et al., 1995), a comprehensive understanding of the genetic, biochemical and cellular mechanisms leading to the formation of neurofibromas has not been clear.
  • Mast cell motility assays in which cellular motility is observed by time lapse imaging of cells exposed to a gradient of growth factor, may also be employed to screen agents.
  • BMMC motility is directly observed by time lapse imaging of cells exposed to a gradient of 10 ng/ml rmSCF in a Dunn chemotaxis chamber (Dunn and Zicha, Dunn & Jones, 1997; Weber Scientific Ltd., Surrey, England).
  • a defined number (e.g., 10 4 - 10 6 ) of BMMCs are resuspended in a volume of medium, e.g., lO ⁇ l RPMI, and are applied to fibronectin fragment H-296 covered glass coverslips.
  • F-actin quantitation may also be performed to screen agents of the invention.
  • Agents of the invention may also be screened by Ras, Cdc42 and Rac activation assays, in which mast cells are stimulated with a growth factor and activation is determined via a commercially available assay kit.
  • BMMCs are deprived of serum and growth factors for 24 hours and stimulated at various amounts of time with a known concentration of growth factor, e.g., 10 ng/ml rmSCF.
  • Ras, Cdc42 and Rac activation is determined using Ras, Cdc42, and Rac activation assay kits (Upstate Biotechnology) according to the manufacturer's protocol and as previously described in Gille and Downward (1999). 9.
  • Ras, Cdc42 and Rac activation assay kits Upstate Biotechnology
  • the active ingredients may be formulated as a lozenge further comprising a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the composition in an inert base such as gelatin and glycerin or sucrose and acacia; mouthwashes comprising the composition of the present invention in a suitable liquid carrier; and pastes and gels, e.g., toothpastes or gels, comprising the composition of the invention.
  • a flavored base usually sucrose and acacia or tragacanth
  • pastilles comprising the composition in an inert base such as gelatin and glycerin or sucrose and acacia
  • mouthwashes comprising the composition of the present invention in a suitable liquid carrier
  • pastes and gels e.g., toothpastes or gels, comprising the composition of the invention.
  • Nfl +/- mice were used to examine the effects of homozygous dismption of Nfl.
  • Nfl -I- embryos die in utero at dl2.5-13.5 p.c. from apparent hydrops fetalis secondary to complex developmental abnormalities of the cardiac system, including overgrowth of the ventricular outflow tracts (Jack et al., 1994).
  • Fetal liver hematopoietic cells were isolated from Nfl -I- embryos prior to their death at day 12.5-13.5 p.c.
  • ERK activity was observed in unstimulated c-kit + cells isolated from the Nfl -I- recipients.
  • this kinase activity increased significantly in Nfl -I- cells after exposure to SCF + IL-3 and persisted above baseline at 5 minutes.
  • c-kit + cells isolated from Nfl +/+ recipients had lower baseline activity and a much less pronounced increase in ERK activity 5 minutes after stimulation compared to Nfl -I- cells.
  • a high concentration of a MEK inhibitor which in turn blocks activation of ERKs, inhibited ERK activity in both Nfl -I- and +/+ cells.
  • Nfl A-I- cells will have a higher percentage of BrdU positive mast cells than Nfl +/+ cells on both a mutant (W) and wildtype c-kit receptor background. Since SCF has been shown to be important for mast cell survival as well as proliferation, it is possible that differences in total numbers of mast cells at local injection sites between genotypes could be in part a result of differences in survival. If differences in total numbers of mast cells at local injection sites are secondary to increased mast cell survival, then the percent of BrdU positive cells (proliferating cells) would be equivalent between experimental groups despite differences in total numbers of mast cells.
  • a second method of evaluating the intrinsic resistance of Nfl +/- cells independent of either growth factor or serum is to evaluate their survival in serum-free and growth factor-free conditioned media.
  • Cells are cultured as described above in 24 well dishes and evaluated for TUNEL positive cells 8, 16, 24, 36, and 48 hours after initiation of cultures and adjusted as indicated from preliminary studies. At least 4-5 independent experiments are conducted for each in vitro measure of apoptosis, and differences between genotypes will be examined using Student's T-test. Evaluation of Survival Advantage of Nfl +/- mast cells in vivo.
  • PAKl or PAK3 is mediating cross-cascade activation of ERK via PI3K to confer a prohferative advantage to Nfl +/- and Nfl -I- mast cells, then transduction of the dominant negative PAKl or PAK 3 cDNAs into Nfl deficient (Nfl -I- or Nfl +/-) cells results in a restoration of normal cytokine responsiveness to SCF in proliferation assays, similar to that observed in wildtype cells.
  • BMMCs were deprived of growth factors for 24 hours and 1 x 10 5 cells were plated in 96 well dishes in 200 ml of RPMI containing 1% glutamine, 10% fetal bovine serum (Hyclone Laboratories) and 100 ng/ml of rmSCF or no growth factors, as indicated, in a 37°C, 5% CO 2 , humidified incubator.
  • Cells were cultured for 48 hours, and tritiated thymidine (New Life Science Products, Inc.) was added to cultures 6 hours prior to harvest. Cells were harvested on glass fiber filters (Packard, Meriden, CT) and ⁇ emission was measured. Assays were performed in triplicate.
  • BMMCs were lysed in nonionic lysis buffer as previously described (Bollag et al., 1996). Cleared lysates were normalized for protein content using the BCA assay (Pierce Chemical Co.) and proteins were immunoprecipitated with protein A sepharose beads (Amersham) coupled with polyclonal antibodies for Raf-1, Mek, PI-3 kinase pi lO ⁇ (H-219) (Santa Cmz), PI-3 kinase pi 10a (H-201) (Santa Cmz), or c-kit (C-19) (Santa Cmz) for 2 hours at 4°C.
  • p21 -activated kinase can mediate crosstalk between PI-3 kinase and the p21 ras -Raf-MEK-ERK pathway by phosphorylating Ser298 on MEKl and Ser338 on Raf-1 (Frost et al., 1997; King et al., 1998). Phosphorylation of Ser298 increases MEKl binding to Raf-1 to enhance the kinase activity of the complex and phosphorylation of Ser338 is critical for Raf- 1 activation in a number of experimental systems (Chaudhary et al., 2000; Frost et al., 1997; King et al., 1998).

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Abstract

La présente invention concerne une méthode pour identifier les inhibiteurs de Raf, MEK, protéine ERK1, protéine ERK2, phosphatidylinositol triphosphate kinase (P13K), protéine PAK2, protéine PAK3, Rac, CDC42, protéine PAK1, protéine kinase B (PKB), Akt, de c-protéine JNK, ou du couplage parasite entre P13-K et le trajet Ras-Raf-MEK-ERK, utilisés pour traiter les troubles tels que la neurofibromatose de type 1, ou au moins un de ses signes cliniques.
PCT/US2000/030924 1999-11-12 2000-11-10 Methodes de detection d'agents utiles pour inhiber la neurofibromatose de type 1 (nf1) WO2001034201A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP00975626A EP1227846A2 (fr) 1999-11-12 2000-11-10 Methodes de detection d'agents utiles pour inhiber la neurofibromatose de type 1 (nf1)
AU13647/01A AU1364701A (en) 1999-11-12 2000-11-10 Methods to detect agents useful to inhibit neurofibromatosis type 1 (nf1)
CA002388343A CA2388343A1 (fr) 1999-11-12 2000-11-10 Methodes de detection d'agents utiles pour inhiber la neurofibromatose de type 1 (nf1)
JP2001536198A JP2003513939A (ja) 1999-11-12 2000-11-10 神経繊維腫症タイプ１（ｎｆ１）の阻害方法

Applications Claiming Priority (2)

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US16521899P 1999-11-12 1999-11-12
US60/165,218 1999-11-12

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WO2001034201A2 true WO2001034201A2 (fr) 2001-05-17
WO2001034201A3 WO2001034201A3 (fr) 2001-12-06
WO2001034201A9 WO2001034201A9 (fr) 2002-07-25

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002006520A1 (fr) * 2000-07-19 2002-01-24 Chugai Seiyaku Kabushiki Kaisha Methode de criblage de compose regulant la transduction de signaux mek/erk et utilisation medicale dudit compose
US7118854B2 (en) * 2001-03-30 2006-10-10 Rigel Pharmaceuticals, Inc. PAK2: modulators of lymphocyte activation
WO2013093137A1 (fr) * 2011-12-20 2013-06-27 Universidad Nacional De Educación A Distancia Composés potentialisateurs de l'apprentissage
US9334332B2 (en) 2012-07-25 2016-05-10 Kolltan Pharmaceuticals, Inc. Anti-kit antibodies
WO2016123086A1 (fr) * 2015-01-26 2016-08-04 Yale University Compositions et procédés d'utilisation d'inhibiteurs de tyrosine kinase
US9540443B2 (en) 2011-01-26 2017-01-10 Kolltan Pharmaceuticals, Inc. Anti-kit antibodies
US10239943B2 (en) 2014-05-23 2019-03-26 Celldex Therapeutics, Inc. Treatment of eosinophil or mast cell related disorders
WO2020053125A1 (fr) * 2018-09-10 2020-03-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés de traitement de la neurofibromatose

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WO1999002701A1 (fr) * 1997-07-11 1999-01-21 Merck & Co., Inc. Genes et polypeptides de kinases pak, et leurs procedes d'utilisation
WO2000059495A1 (fr) * 1999-04-02 2000-10-12 Temple University - Of The Commonwealth System Of Higher Education Agents anticancer au (e)-styrylsulfone

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO1999002701A1 (fr) * 1997-07-11 1999-01-21 Merck & Co., Inc. Genes et polypeptides de kinases pak, et leurs procedes d'utilisation
WO2000059495A1 (fr) * 1999-04-02 2000-10-12 Temple University - Of The Commonwealth System Of Higher Education Agents anticancer au (e)-styrylsulfone

Non-Patent Citations (3)

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Title
GUTMANN D H ET AL: "Haploinsufficiency for the neurofibromatosis 1 ( NF1 ) tumor suppressor results in increased astrocyte proliferation." ONCOGENE, (1999 AUG 5) 18 (31) 4450-9. , XP000985616 *
TANG Y ET AL: "A role for Pak protein kinases in Schwann cell transformation." PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, (1998 APR 28) 95 (9) 5139-44. , XP002165279 *
TANG YI ET AL: "Kinase-deficient Pak1 mutants inhibit Ras transformation of Rat-1 fibroblasts." MOLECULAR AND CELLULAR BIOLOGY, vol. 17, no. 8, 1997, pages 4454-4464, XP002165280 ISSN: 0270-7306 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002006520A1 (fr) * 2000-07-19 2002-01-24 Chugai Seiyaku Kabushiki Kaisha Methode de criblage de compose regulant la transduction de signaux mek/erk et utilisation medicale dudit compose
US7118854B2 (en) * 2001-03-30 2006-10-10 Rigel Pharmaceuticals, Inc. PAK2: modulators of lymphocyte activation
US10189907B2 (en) 2011-01-26 2019-01-29 Celldex Therapeutics, Inc. Polynucleotides encoding anti-KIT antibodies
US11884699B2 (en) 2011-01-26 2024-01-30 Celldex Therapeutics, Inc. Anti-KIT antibodies and uses thereof
US10793639B2 (en) 2011-01-26 2020-10-06 Celldex Therapeutics, Inc. Methods of treating by administering anti-kit antibodies
US9540443B2 (en) 2011-01-26 2017-01-10 Kolltan Pharmaceuticals, Inc. Anti-kit antibodies
WO2013093137A1 (fr) * 2011-12-20 2013-06-27 Universidad Nacional De Educación A Distancia Composés potentialisateurs de l'apprentissage
ES2415581A1 (es) * 2011-12-20 2013-07-25 Universidad Nacional De Educación A Distancia Compuestos potenciadores del aprendizaje.
US10781267B2 (en) 2012-07-25 2020-09-22 Celldex Therapeutics, Inc. Methods of treating by administering anti-kit antibodies
US10184007B2 (en) 2012-07-25 2019-01-22 Celldex Therapeutics, Inc. Methods of treating a kit-associated cancer by administering anti-kit antibodies
US9605081B2 (en) 2012-07-25 2017-03-28 Celldex Therapeutics, Inc. Polynucleotides encoding anti-kit antibodies
US9334332B2 (en) 2012-07-25 2016-05-10 Kolltan Pharmaceuticals, Inc. Anti-kit antibodies
US11891452B2 (en) 2012-07-25 2024-02-06 Celldex Therapeutics, Inc. Anti-kit antibodies and uses thereof
US10239943B2 (en) 2014-05-23 2019-03-26 Celldex Therapeutics, Inc. Treatment of eosinophil or mast cell related disorders
US10774146B2 (en) 2014-05-23 2020-09-15 Celldex Therapeutics, Inc. Treatment of eosinophil or mast cell related disorders
US11987626B2 (en) 2014-05-23 2024-05-21 Celldex Therapeutics, Inc. Treatment of eosinophil or mast cell related disorders
CN107530298A (zh) * 2015-01-26 2018-01-02 耶鲁大学 利用酪氨酸激酶抑制剂的组合物和方法
US10471059B2 (en) 2015-01-26 2019-11-12 Yale University Compositions and methods of using tyrosine kinase inhibitors
WO2016123086A1 (fr) * 2015-01-26 2016-08-04 Yale University Compositions et procédés d'utilisation d'inhibiteurs de tyrosine kinase
US11458137B2 (en) 2015-01-26 2022-10-04 Yale University Compositions and methods of using tyrosine kinase inhibitors
WO2020053125A1 (fr) * 2018-09-10 2020-03-19 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédés de traitement de la neurofibromatose

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Publication number Publication date
AU1364701A (en) 2001-06-06
WO2001034201A3 (fr) 2001-12-06
CA2388343A1 (fr) 2001-05-17
WO2001034201A9 (fr) 2002-07-25
JP2003513939A (ja) 2003-04-15
EP1227846A2 (fr) 2002-08-07

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