Method for treating skeletal disorders resulting from FGFR...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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Details

C514S277000, C514S279000, C514S299000, C514S359000, C514S408000, C514S410000, C514S412000, C546S113000

Reexamination Certificate

active

07872016

ABSTRACT:
The invention provides materials, reagents, systems, and methods for identifying agents useful for treating diseases resulting from abnormal (e.g., excessive) FGF receptor signaling. The invention also provides (therapeutic) agents thus identified, and methods of using such agents in treating such diseases. In certain embodiments, the invention relates to the treatment of various craniofacial disorders, or Craniosynostosis, that result from FGFR (e.g. FGFR2) malfunction, such as Crouzon, Apert, Jackson-Weiss, Pfeiffer Syndromes, Crouzon+acanthosis nigricans, Beare-Stevenson cutis gyrata, and non-syndromic craniosynostosis (NS). The methods comprise administering to the individuals a therapeutically effective amount of an inhibitor of the FGFR2c-FRS2 signaling. The inhibitor inhibits signaling by antagonizing FGFR2c-FRS2 interaction, inhibiting the expression and/or subcellular localization of wild-type or mutant FGFR2c and/or FRS2, inhibiting the kinase activity of FGFR2c (e.g. for autophosphorylation and/or phosphorylation of FRS2), and/or inhibiting downstream signaling of FRS2 (such as Sos-Ras-MAPK, Shp2, and/or Gab 1-PI3K pathways).

REFERENCES:
patent: 2002/0086972 (2002-07-01), Kouhara et al.
patent: 1332761 (2003-08-01), None
patent: WO 01/04160 (2001-01-01), None
patent: WO 03/076467 (2003-09-01), None
Arman et al., “Fgfr2 is Reuired for Limb Outgrowth and lung-Branching Morphongenesis,” Proceedings of the national Academy of Science of USA 96(21):11895-11899 (1999).
Dailey et al., “Mechanisms Underlying Differential Responses to FGF Signaling,” Cytokine and Growth Factor Reviews 16(2):233-247 (2005).
Eswarakumar et al., “Cellular Signaling by Fibroblast Growth Factor Receoptors,” Cytokine and Growth Factor Reviews 16(2)139-149 (2005).
Mansukhani et al., “Signaling by Fibroblast Growth Factors (FGF) and Fibroblast Growth Factor Receoptor 2 (FGFR2)-Activating Mutations Blocks Mineralization and Induces Apoptosis in Osteoblasts,” The Journal of Cell Biology, Rockefeller University Press 149(6):1297-1308 (2000).
Mood et al., “SNT1/FRS2 Mediates Germinal Vesicle Breakdown Induced by an Activated FGF Receptor 1 in Xenopus Oocytes,” Journal of Biological chemistry 277(36):33196-33204 (2002).

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