Title:
THERAPEUTIC AGENT FOR SYSTEMIC BONE DISEASE AND USE THEREOF
Document Type and Number:
WIPO Patent Application WO/2014/141847
Kind Code:
A1
Abstract:
The present invention addresses the problem of providing a novel therapeutic strategy which has excellent therapeutic effects on systemic bone diseases caused by over-activation of FGFR3, in particular, achondroplasia and hypochondroplasia. A therapeutic agent for systemic bone disease is provided which comprises, as an active ingredient, meclizine or a pharmaceutically acceptable salt thereof.
Inventors:
OHNO KINJI (JP)
ISHIGURO NAOKI (JP)
KITO HIROSHI (JP)
MATSUSHITA MASAKI (JP)
ISHIGURO NAOKI (JP)
KITO HIROSHI (JP)
MATSUSHITA MASAKI (JP)
Application Number:
PCT/JP2014/054023
Publication Date:
September 18, 2014
Filing Date:
February 20, 2014
Export Citation:
Assignee:
UNIV NAGOYA NAT UNIV CORP (JP)
International Classes:
A61K31/495; A23L1/30; A61P19/00; A61P43/00
Domestic Patent References:
| WO2007061130A1 | 2007-05-31 |
Foreign References:
| JPH08239327A | 1996-09-17 | |||
| JP2008533111A | 2008-08-21 | |||
| JP2009520768A | 2009-05-28 | |||
| JPH11507828A | 1999-07-13 | |||
| JP2011504506A | 2011-02-10 | |||
| JP2003104908A | 2003-04-09 |
Other References:
MASAKI MATSUSHITA ET AL.: "Meclozine Facilitates Proliferation and Differentiation of Chondrocytes by Attenuating Abnormally Activated FGFR3 Signaling in Achondroplasia", PLOS ONE, vol. 8, no. 12, pages 1 - 9, XP055197847
"Norimonoyoi OTC-yaku Meclozine no Off-label Kono ni yoru Teishinchosho no Chiryo", PRESS RELEASE NAGOYA UNIVERSITY, [ON LINE], 5 December 2013 (2013-12-05), XP055198239
MASAKI MATSUSHITA ET AL.: "Meclozine wa Nankotsu Mukeiseisho ni Okeru FGFR3 Signal ni yoru Nankotsu Saibo no Zoshoku Bunka Yokusei o Rescue suru", THE JOURNAL OF THE JAPANESE ORTHOPAEDIC ASSOCIATION, vol. 87, no. 8, 30 August 2013 (2013-08-30), pages S1322, XP008176986
See also references of EP 2985024A4
KREJCI, P.; MURAKAMI, S.; PROCHAZKOVA, J.; TRANTIREK, L.; CHLEBOVA, K.; OUYANG, Z.; AKLIAN, A.; SMUTNY, J.; BRYJA, V.; KOZUBIK, A.: "NF449 is a novel inhibitor of fibroblast growt h factor receptor 3 (FGFR3) signaling active in chondrocytes and multiple myeloma cells", J. BIOL. CHEM., vol. 285, 2010, pages 20644 - 20653, XP002673700, DOI: doi:10.1074/JBC.M109.083626
JIN, M.; YU, Y.; QI, H.; XIE, Y.; SU, N.; WANG, X.; TAN, Q.; LUO, F.; ZHU, Y.; WANG, Q. ET AL.: "A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the lethal phenoty pe of mice mimicking human thanatophoric dysplasia", HUM. MOL. GENET., vol. 21, 2012, pages 5443 - 5455, XP055073426, DOI: doi:10.1093/hmg/dds390
JONQUOY, A.; MUGNIERY, E.; BENOIST-LASSELIN, C.; KACI, N.; LE CORRE, L.; BARBAULT, F.; GIRARD, A.L.; LE MERRER, Y.; BUSCA, P.; SCH: "A novel tyrosine kinase inhibitor resto res chondrocyte differentiation and promotes bone growth in a gain-of-function Fgfr3 mouse model", HUM. MOL. GENET., vol. 21, 2012, pages 841 - 851
KREJCI, P.; MASRI, B.; FONTAINE, V.; MEKIKIAN, P.B.; WEIS, M.; PRATS, H.; WILCOX, W.R.: "Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regulation of ch ondrocyte proliferation and extracellular matrix homeostasis", J. CELL SCI., vol. 118, 2005, pages 5089 - 5100, XP055167110, DOI: doi:10.1242/jcs.02618
YASODA, A.; KOMATSU, Y.; CHUSHO, H.; MIYAZAWA, T.; OZASA, A.; MIURA, M.; KURIHARA, T.; ROGI, T.; TANAKA, S.; SUDA, M. ET AL.: "Overexpression of CNP in chondrocytes rescues achond roplasia through a MAPK-dependent pathway", NAT. MED., vol. 10, 2004, pages 80 - 86
YASODA, A.; KITAMURA, H.; FUJII, T.; KONDO, E.; MURAO, N.; MIURA, M.; KANAMOTO, N.; KOMATSU , Y.; ARAI, H.; NAKAO, K.: "Systemic administration ofC-type natriuretic peptide as a novel therapeutic strategy for skeletal dysplasias", ENDOCRINOLOGY, vol. 150, 2009, pages 3138 - 3144, XP008110039, DOI: doi:10.1210/en.2008-1576
LORGET, F.; KACI, N.; PENG, J.; BENOIST-LASSELIN, C.; MUGNIERY, E.; OPPENEER, T.; WENDT, D.J.; B ELL, S.M.; BULLENS, S.; BUNTING,: "Evaluation of the therapeutic potential of a CN P analog in a Fgfr3 mouse model recapitulating achondroplasia", AM J HUM GENET, vol. 91, 2012, pages 1108 - 1 114
TSUNEKI SU GIHARA: "ADVANCE SERIES II-9", KOKUSEIDO CO., LTD., article "Hone Enchojutsu Saikin No Shinpo (Bone Lengthening: Rec ent advance)"
WALLER, D.K.; CORREA, A.; VO, T.M.; WANG, Y.; HOBBS, C.; LANGLOIS, P.H.; PEARSON, K.; ROMITTI, P.A.; SHAW, G.M.; HECHT, J.T.: "The population-based prevalence of acho ndroplasia and thanatophoric dysplasia in selected regions of the US", AM J MED GENET A, vol. 146 A, 2008, pages 2385 - 2389
HORTON, W.A.; HALL, J.G.; HECHT, J.T.: "Achondroplasia", LANCET, vol. 370, 2007, pages 162 - 172, XP022152775, DOI: doi:10.1016/S0140-6736(07)61090-3
ROUSSEAU, F.; BONAVENTURE, J.; LEGEAI-MALLET, L.; PELET, A.; ROZET, J.M.; MAROTEAUX , P.; LE MERRER, M.; MUNNICH, A.: "Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia", NATURE, vol. 371, 1994, pages 252 - 254, XP002071230, DOI: doi:10.1038/371252a0
SHIANG, R.; THOMPSON, L.M.; ZHU, Y.Z.; CHURCH, D.M.; FIELDER, T.J.; BOCIAN, M.; WINOKUR, S.T.; WASMUTH, J.J.: "Mutations in the transmembrane domain of FGFR3 c ause the most common genetic form of dwarfism, achondroplasia", CELL, vol. 78, 1994, pages 335 - 342, XP024245673, DOI: doi:10.1016/0092-8674(94)90302-6
KREJCI, P.; BRYJA, V.; PACHERNIK, J.; HAMPL, A.; POGUE, R.; MEKIKIAN, P.; WILCOX, W.R.: "FGF2 inhibits proliferation and alters the cartilage-like phenotype of RCS cells", EXP. CELL RES., vol. 297, 2004, pages 152 - 164
KREJCI, P.; MASRI, B.; FONTAINE, V.; MEKIKIAN, P.B.; WEIS, M.; PRATS, H.; WILCOX, W.R.: "Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regu lation of chondrocyte proliferation and extracellular matrix homeostasis", J. CELL SCI., vol. 118, no. 508, 2005, pages 9 - 5100
MURAKAMI, S.; BALMES, G.; MCKINNEY, S.; ZHANG, Z.; GIVOL, D.; DE CROMBRUGGH E, B.: "Constitutive activation ofMEKl in chondrocytes causes Statl-independent achon droplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype", GENES DEV., vol. 18, no. 29, 2004, pages 0 - 305
PRINOS, P.; COSTA, T.; SOMMER, A.; KILPATRICK, M.W.; TSIPOURAS, P.: "A com mon FGFR3 gene mutation in hypochondroplasia", HUM. MOL. GENET., vol. 4, 1995, pages 2097 - 2101
TAVORMINA, P.L.; BELLUS, G.A.; WEBSTER, M.K.; BAMSHAD, M.J.; FRALEY, A.E.; MCINTO SH, 1.; SZABO, J.; JIANG, W.; JABS, E.W.; WILCOX: "A novel skeletal dysplasia wi th developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fib roblast growth factor receptor 3 gene", AM J HUM GENET, vol. 64, 1999, pages 722 - 731
TAVORMINA, P.L.; SHIANG, R.; THOMPSON, L.M.; ZHU, Y.Z.; WILKIN, D.J.; LACHMAN, R.S.; WILCOX, W.R.; RIMOIN, D.L.; COHN, D.H.; WASMU: "Thanatophoric dyspl asia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3", NAT. G ENET., vol. 9, 1995, pages 321 - 328
TOYDEMIR, R.M.; BRASSINGTON, A.E.; BAYRAK-TOYDEMIR, P.; KRAKOWIAK, P.A.; JORDE, L.B.; WHITBY, F.G.; LONGO, N.; VISKOCHIL, D.H.; CA: "A nove 1 mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrom e", AM J HUM GENET, vol. 79, 2006, pages 935 - 941
BEEVER, J.E.; SMIT, M.A.; MEYERS, S.N.; HADFIELD, T.S.; BOTTEMA, C.; ALBRETSEN, J.; COCKETT, N.E.: "A single-base change in the tyrosine kinase II domain of ovine FGF R3 causes hereditary chondrodysplasia in sheep", ANIM. GENET., vol. 37, 2006, pages 66 - 71
HORTON, W.A.; HECHT, J.T.; HOOD, O.J.; MARSHALL, R.N.; MOORE, WV.; HOLLOWEL 1, J.G.: "Growth hormone therapy in achondroplasia", AM. J. MED. GENET., vol. 42, 1992, pages 667 - 670
KREJCI, P.; MURAKAMI, S.; PROCHAZKOVA, J.; TRANTIREK, L.; CHLEBOVA, K.; OUYANG, Z; AKLIAN, A.; SMUTNY, J.; BRYJA, V.; KOZUBIK, A.: "NF449 is a novel inhibitor offibr oblast growth factor receptor 3 (FGFR3) signaling active in chondrocytes and multiple myelo ma cells", J. BIOL. CHEM., vol. 285, 2010, pages 20644 - 20653
JIN, M.; YU, Y.; QI, H.; XIE, Y.; SU, N.; WANG, X.; TAN, Q.; LUO, F.; ZHU, Y.; WANG, Q. ET AL.: "A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the let hal phenotype of mice mimicking human thanatophoric dysplasia", HUM. MOL. GENET., vol. 21, no. 544, 2012, pages 3 - 5455
JONQUOY, A.; MUGNIERY, E; BENOIST-LASSELIN, C.; KACI, N.; LE CORRE, L.; BARBAULT, F.; GIRARD, A.L.; LE MERRER, Y.; BUSCA, P.; SCHI: "A novel tyrosine kinase inh ibitor restores chondrocyte differentiation and promotes bone growth in a gain-of-function Fgf r3 mouse model", HUM. MOL. GENET., vol. 21, 2012, pages 841 - 851
YASODA, A.; KOMATSU, Y.; CHUSHO, H.; MIYAZAWA, T.; OZASA, A.; MIURA, M.; KURIH ARA, T.; ROGI, T.; TANAKA, S.; SUDA, M. ET AL.: "Overexpression of CNP in chondrocytes re scues achondroplasia through a MAPK-dependent pathway", NAT. MED., vol. 10, 2004, pages 80 - 86, XP002539064, DOI: doi:10.1038/nm971
YASODA, A.; KITAMURA, H.; FUJII, T.; KONDO, E.; MURAO, N.; MIURA, M.; KANAMOTO, N.; KOMATSU, Y.; ARAI, H.; NAKAO, K.: "Systemic administration ofC-type natriuretic peptide as a novel therapeutic strategy for skeletal dysplasias", ENDOCRINOLOGY, vol. 150, 2009, pages 3138 - 3144, XP008110039, DOI: doi:10.1210/en.2008-1576
LORGET, F.; KACI, N.; PENG, J.; BENOIST-LASSELIN, C.; MUGNIERY, E.; OPPENEER, T.; W ENDT, D.J.; BELL, S.M.; BULLENS, S.; BUNTING,: "Evaluation of the therapeutic poten tial of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia", AM J HUM GENET, vol. 91, 2012, pages 1108 - 1114
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CHUSHO, H.; TAMURA, N.; OGAWA, Y.; YASODA, A.; SUDA, M.; MIYAZAWA, T.; NAKAM URA, K.; NAKAO, K.; KURIHARA, T.; KOMATSU, Y ET AL.: "Dwarfism and early death in mice 1 acking C-type natriuretic peptide", PROC. NATL. ACAD. SCI. U. S. A., vol. 98, 2001, pages 4016 - 4021, XP002982869, DOI: doi:10.1073/pnas.071389098
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GOHIL, V.M.; SHETH, S.A.; NILSSON, R.; WOJTOVICH, A.P.; LEE, J.H.; PEROCCHI, F.; CH EN, W.; CLISH, C.B.; AYATA, C.; BROOKES, P.S.: "Nutrient-sensitized screening for dru gs that shift energy metabolism from mitochondrial respiration to glycolysis", NAT. BIOTECHNOL., vol. 28, 2010, pages 249 - 255
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KREJCI, P.; MASRI, B.; SALAZAR, L.; FARRINGTON-ROCK, C.; PRATS, H.; THOMPSON, L.M.; WILCOX, W.R.: "Bisindolylmaleimide I suppresses fibroblast growth factor-mediated activation ofErk MAP kinase in chondrocytes by preventing Shp2 association with the Frs2 a nd Gabl adaptor proteins", J. BIOL. CHEM., vol. 282, 2007, pages 2929 - 2936
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"Norimonoyoi OTC-yaku Meclozine no Off-label Kono ni yoru Teishinchosho no Chiryo", PRESS RELEASE NAGOYA UNIVERSITY, [ON LINE], 5 December 2013 (2013-12-05), XP055198239
MASAKI MATSUSHITA ET AL.: "Meclozine wa Nankotsu Mukeiseisho ni Okeru FGFR3 Signal ni yoru Nankotsu Saibo no Zoshoku Bunka Yokusei o Rescue suru", THE JOURNAL OF THE JAPANESE ORTHOPAEDIC ASSOCIATION, vol. 87, no. 8, 30 August 2013 (2013-08-30), pages S1322, XP008176986
See also references of EP 2985024A4
KREJCI, P.; MURAKAMI, S.; PROCHAZKOVA, J.; TRANTIREK, L.; CHLEBOVA, K.; OUYANG, Z.; AKLIAN, A.; SMUTNY, J.; BRYJA, V.; KOZUBIK, A.: "NF449 is a novel inhibitor of fibroblast growt h factor receptor 3 (FGFR3) signaling active in chondrocytes and multiple myeloma cells", J. BIOL. CHEM., vol. 285, 2010, pages 20644 - 20653, XP002673700, DOI: doi:10.1074/JBC.M109.083626
JIN, M.; YU, Y.; QI, H.; XIE, Y.; SU, N.; WANG, X.; TAN, Q.; LUO, F.; ZHU, Y.; WANG, Q. ET AL.: "A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the lethal phenoty pe of mice mimicking human thanatophoric dysplasia", HUM. MOL. GENET., vol. 21, 2012, pages 5443 - 5455, XP055073426, DOI: doi:10.1093/hmg/dds390
JONQUOY, A.; MUGNIERY, E.; BENOIST-LASSELIN, C.; KACI, N.; LE CORRE, L.; BARBAULT, F.; GIRARD, A.L.; LE MERRER, Y.; BUSCA, P.; SCH: "A novel tyrosine kinase inhibitor resto res chondrocyte differentiation and promotes bone growth in a gain-of-function Fgfr3 mouse model", HUM. MOL. GENET., vol. 21, 2012, pages 841 - 851
KREJCI, P.; MASRI, B.; FONTAINE, V.; MEKIKIAN, P.B.; WEIS, M.; PRATS, H.; WILCOX, W.R.: "Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regulation of ch ondrocyte proliferation and extracellular matrix homeostasis", J. CELL SCI., vol. 118, 2005, pages 5089 - 5100, XP055167110, DOI: doi:10.1242/jcs.02618
YASODA, A.; KOMATSU, Y.; CHUSHO, H.; MIYAZAWA, T.; OZASA, A.; MIURA, M.; KURIHARA, T.; ROGI, T.; TANAKA, S.; SUDA, M. ET AL.: "Overexpression of CNP in chondrocytes rescues achond roplasia through a MAPK-dependent pathway", NAT. MED., vol. 10, 2004, pages 80 - 86
YASODA, A.; KITAMURA, H.; FUJII, T.; KONDO, E.; MURAO, N.; MIURA, M.; KANAMOTO, N.; KOMATSU , Y.; ARAI, H.; NAKAO, K.: "Systemic administration ofC-type natriuretic peptide as a novel therapeutic strategy for skeletal dysplasias", ENDOCRINOLOGY, vol. 150, 2009, pages 3138 - 3144, XP008110039, DOI: doi:10.1210/en.2008-1576
LORGET, F.; KACI, N.; PENG, J.; BENOIST-LASSELIN, C.; MUGNIERY, E.; OPPENEER, T.; WENDT, D.J.; B ELL, S.M.; BULLENS, S.; BUNTING,: "Evaluation of the therapeutic potential of a CN P analog in a Fgfr3 mouse model recapitulating achondroplasia", AM J HUM GENET, vol. 91, 2012, pages 1108 - 1 114
TSUNEKI SU GIHARA: "ADVANCE SERIES II-9", KOKUSEIDO CO., LTD., article "Hone Enchojutsu Saikin No Shinpo (Bone Lengthening: Rec ent advance)"
WALLER, D.K.; CORREA, A.; VO, T.M.; WANG, Y.; HOBBS, C.; LANGLOIS, P.H.; PEARSON, K.; ROMITTI, P.A.; SHAW, G.M.; HECHT, J.T.: "The population-based prevalence of acho ndroplasia and thanatophoric dysplasia in selected regions of the US", AM J MED GENET A, vol. 146 A, 2008, pages 2385 - 2389
HORTON, W.A.; HALL, J.G.; HECHT, J.T.: "Achondroplasia", LANCET, vol. 370, 2007, pages 162 - 172, XP022152775, DOI: doi:10.1016/S0140-6736(07)61090-3
ROUSSEAU, F.; BONAVENTURE, J.; LEGEAI-MALLET, L.; PELET, A.; ROZET, J.M.; MAROTEAUX , P.; LE MERRER, M.; MUNNICH, A.: "Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia", NATURE, vol. 371, 1994, pages 252 - 254, XP002071230, DOI: doi:10.1038/371252a0
SHIANG, R.; THOMPSON, L.M.; ZHU, Y.Z.; CHURCH, D.M.; FIELDER, T.J.; BOCIAN, M.; WINOKUR, S.T.; WASMUTH, J.J.: "Mutations in the transmembrane domain of FGFR3 c ause the most common genetic form of dwarfism, achondroplasia", CELL, vol. 78, 1994, pages 335 - 342, XP024245673, DOI: doi:10.1016/0092-8674(94)90302-6
KREJCI, P.; BRYJA, V.; PACHERNIK, J.; HAMPL, A.; POGUE, R.; MEKIKIAN, P.; WILCOX, W.R.: "FGF2 inhibits proliferation and alters the cartilage-like phenotype of RCS cells", EXP. CELL RES., vol. 297, 2004, pages 152 - 164
KREJCI, P.; MASRI, B.; FONTAINE, V.; MEKIKIAN, P.B.; WEIS, M.; PRATS, H.; WILCOX, W.R.: "Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regu lation of chondrocyte proliferation and extracellular matrix homeostasis", J. CELL SCI., vol. 118, no. 508, 2005, pages 9 - 5100
MURAKAMI, S.; BALMES, G.; MCKINNEY, S.; ZHANG, Z.; GIVOL, D.; DE CROMBRUGGH E, B.: "Constitutive activation ofMEKl in chondrocytes causes Statl-independent achon droplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype", GENES DEV., vol. 18, no. 29, 2004, pages 0 - 305
PRINOS, P.; COSTA, T.; SOMMER, A.; KILPATRICK, M.W.; TSIPOURAS, P.: "A com mon FGFR3 gene mutation in hypochondroplasia", HUM. MOL. GENET., vol. 4, 1995, pages 2097 - 2101
TAVORMINA, P.L.; BELLUS, G.A.; WEBSTER, M.K.; BAMSHAD, M.J.; FRALEY, A.E.; MCINTO SH, 1.; SZABO, J.; JIANG, W.; JABS, E.W.; WILCOX: "A novel skeletal dysplasia wi th developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fib roblast growth factor receptor 3 gene", AM J HUM GENET, vol. 64, 1999, pages 722 - 731
TAVORMINA, P.L.; SHIANG, R.; THOMPSON, L.M.; ZHU, Y.Z.; WILKIN, D.J.; LACHMAN, R.S.; WILCOX, W.R.; RIMOIN, D.L.; COHN, D.H.; WASMU: "Thanatophoric dyspl asia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3", NAT. G ENET., vol. 9, 1995, pages 321 - 328
TOYDEMIR, R.M.; BRASSINGTON, A.E.; BAYRAK-TOYDEMIR, P.; KRAKOWIAK, P.A.; JORDE, L.B.; WHITBY, F.G.; LONGO, N.; VISKOCHIL, D.H.; CA: "A nove 1 mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrom e", AM J HUM GENET, vol. 79, 2006, pages 935 - 941
BEEVER, J.E.; SMIT, M.A.; MEYERS, S.N.; HADFIELD, T.S.; BOTTEMA, C.; ALBRETSEN, J.; COCKETT, N.E.: "A single-base change in the tyrosine kinase II domain of ovine FGF R3 causes hereditary chondrodysplasia in sheep", ANIM. GENET., vol. 37, 2006, pages 66 - 71
HORTON, W.A.; HECHT, J.T.; HOOD, O.J.; MARSHALL, R.N.; MOORE, WV.; HOLLOWEL 1, J.G.: "Growth hormone therapy in achondroplasia", AM. J. MED. GENET., vol. 42, 1992, pages 667 - 670
KREJCI, P.; MURAKAMI, S.; PROCHAZKOVA, J.; TRANTIREK, L.; CHLEBOVA, K.; OUYANG, Z; AKLIAN, A.; SMUTNY, J.; BRYJA, V.; KOZUBIK, A.: "NF449 is a novel inhibitor offibr oblast growth factor receptor 3 (FGFR3) signaling active in chondrocytes and multiple myelo ma cells", J. BIOL. CHEM., vol. 285, 2010, pages 20644 - 20653
JIN, M.; YU, Y.; QI, H.; XIE, Y.; SU, N.; WANG, X.; TAN, Q.; LUO, F.; ZHU, Y.; WANG, Q. ET AL.: "A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the let hal phenotype of mice mimicking human thanatophoric dysplasia", HUM. MOL. GENET., vol. 21, no. 544, 2012, pages 3 - 5455
JONQUOY, A.; MUGNIERY, E; BENOIST-LASSELIN, C.; KACI, N.; LE CORRE, L.; BARBAULT, F.; GIRARD, A.L.; LE MERRER, Y.; BUSCA, P.; SCHI: "A novel tyrosine kinase inh ibitor restores chondrocyte differentiation and promotes bone growth in a gain-of-function Fgf r3 mouse model", HUM. MOL. GENET., vol. 21, 2012, pages 841 - 851
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Attorney, Agent or Firm:
HAGINO Mikiharu (JP)
Kanji Hagino (JP)
Kanji Hagino (JP)
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