| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T91331 | ||||
| Target Name | FGF-3 receptor | ||||
| Target Type | Clinical Trial |
||||
| Drug Potency against Target | AEE-788 | Drug Info | IC50 = 6 nM | [552727] | |
| TKI258 | Drug Info | Ki = 8 nM | [552978] | ||
| Ro-4396686 | Drug Info | IC50 = 92 nM | [528018] | ||
| 5,11-Dimethyl-6H-pyrido[4,3-b]carbazol-9-ol | Drug Info | IC50 = 400 nM | [527769] | ||
| PD-0183812 | Drug Info | IC50 = 8620 nM | [525924] | ||
| Action against Disease Model | AEE-788 | AEE788 inhibited EGFR and VEGF receptor tyrosine kinases in the nm range (IC(50)s: EGFR 2 nm, ErbB2 6 nm, KDR 77 nm, and Flt-1 59 nm). In cells, growth factor-induced EGFR and ErbB2 phosphorylation was also efficiently inhibited (IC(50)s: 11 and 220 nm, respectively). AEE788 demonstrated antiproliferative activity against a range of EGFR and ErbB2-overexpressing cell lines (including EGFRvIII-dependent lines) and inhibited the proliferation of epidermal growth factor- and VEGF-stimulated h uMan uMbilical vein endothelial cells. | [552448] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | Achondroplasia, the most common form of dwarfism in man, is a dominant genetic disorder caused by a point mutation (G380R) in the transmembrane region of fibroblast growth factor receptor 3 (FGFR3). We used gene targeting to introduce the h uMan achondroplasia mutation into the murine FGFR3 gene. Heterozygotes for this point mutation that carried the neo cassette were normalwhereas neo+ homozygotes had a phenotype similar to FGFR3-deficient mice, exhibiting bone overgrowth. This was because of interference with mRNA processing in the presence of the neo cassette. Removal of the neo selection marker by Cre/loxP recombination yielded a dominant dwarf phenotype. These mice are distinguished by their small size, shortened craniofacial area, hypoplasia of the midface with protruding incisors, distorted brain case with anteriorly shifted foramen magn uM, kyphosis, and narrowed and distorted growth plates in the long bones, vertebrae, and ribs. These experiments demonstrate that achondroplasia results from a gain-of-FGFR3-function leading to inhibition of chondrocyte proliferation. These achondroplastic dwarf mice represent a reliable and useful model for developing drugs for potential treatment of the h uMan disease | [552727] | |||
| References | |||||
| Ref 552727 | Molecular design and clinical development of VEGFR kinase inhibitors. Curr Top Med Chem. 2007;7(14):1379-93. | ||||
| Ref 552448 | AEE788: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 2004 Jul 15;64(14):4931-41. | ||||
| Ref 552978 | An overview of small-molecule inhibitors of VEGFR signaling. Nat Rev Clin Oncol. 2009 Oct;6(10):569-79. doi: 10.1038/nrclinonc.2009.130. Epub 2009 Sep 8. | ||||
| Ref 528018 | Bioorg Med Chem Lett. 2006 Apr 1;16(7):1950-3. Epub 2006 Feb 3.Biological evaluation of a multi-targeted small molecule inhibitor of tumor-induced angiogenesis. | ||||
| Ref 527769 | J Med Chem. 2005 Oct 6;48(20):6194-201.Molecular modeling of wild-type and D816V c-Kit inhibition based on ATP-competitive binding of ellipticine derivatives to tyrosine kinases. | ||||
| Ref 525924 | J Med Chem. 2000 Nov 30;43(24):4606-16.Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases. | ||||
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