Informace o projektu
High-throughput screening of compound libraries aimed on discovery of novel inhibitors of the FGFR/ERK MAP kinase signaling
(HTS-FGFR)
- Kód projektu
- MUNI/M/0071/2013
- Období řešení
- 4/2013 - 12/2015
- Investor / Programový rámec / typ projektu
-
Masarykova univerzita
- Grantová agentura MU
- INTERDISCIPLINARY - Mezioborové výzkumné projekty
- Fakulta / Pracoviště MU
- Lékařská fakulta
- Další fakulta/pracoviště MU
- Fakulta informatiky
Fibroblast growth factor receptor (FGFR)/ERK MAP kinase signaling pathway is often deregulated in human disperse and therefore constitutes a major target for therapeutic intervention. While several small compound inhibitors exist to target FGFR/ERK signaling, they show only a limited use in clinic, warranting development of novel treatment strategies. Cell-based high-throughput screening (HTS) of chemical libraries represents one effective approach for identification of novel compounds affecting the signaling pathways. Compared to biochemical assays based on the protein-protein or protein-chemical interaction, the cell-based approach offers an advantage to identify modulators of entire pathway in intact cell invironment, complete with regulatory networks and feedback control mechanisms. The major disadvantage of the assays based on cell growth is high false-positive rate, i.e. toxic compounds as well as those targeting other pro-growth pathways will be picked up. We propose to overcome the latter by utilizing cell growth-arrest instead of proliferation as a reporter for HTS screening. In our previous work we characterized, in detail, the molecular features of FGFR/ERK-mediated growth arrest in rat chondrosarcoma (RCS) cells, including the proof-of-concept experiments demonstrating the potential of RCS growth-arrest assay for discovery of novel FGFR/ERK inhibitors. Here, we propose to develop and successfully apply the RCS growth-arrest assay for image-based screening of large chemical libraries aimed on discovery and further characterization of novel, potentially therapeutic inhibitors of pathological FGFR/ERK signaling. Subsequently, we will combine modern methods of molecular biology, genetics and biological approaches to identify the targeted proteins and characterize the molecular mechanism of inhibition. Finally, we will combine several in vivo approaches to determine the basic pharmacological properties of the lead compounds identified in screenings, and to validate their therapeutic potential in preclinical models to pathological FGFR/ERK signaling.
Publikace
Počet publikací: 10
2017
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One reporter for in-cell activity profiling of majority of protein kinase oncogenes
eLife, rok: 2017, ročník: 6, vydání: "e21536", DOI
2016
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An inactivating mutation in intestinal cell kinase, ICK, impairs hedgehog signalling and causes short rib-polydactyly syndrome
Human Molecular Genetics, rok: 2016, ročník: 25, vydání: 18, DOI
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Multikinase activity of fibroblast growth factor receptor (FGFR) inhibitors SU5402, PD173074, AZD1480, AZD4547 and BGJ398 compromises the use of small chemicals targeting FGFR catalytic activity for therapy of short stature syndromes
Human Molecular Genetics, rok: 2016, ročník: 25, vydání: 1, DOI
2015
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A novel variant of FGFR3 causes proportionate short stature
European Journal od Endocrinology, rok: 2015, ročník: 172, vydání: 6, DOI
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Automated Cell Segmentation in Phase-Contrast Images based on Classification and Region Growing
Proceedings of 2015 IEEE International Symposium on Biomedical Imaging, 2015., rok: 2015
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Fibroblast growth factor and canonical WNT/beta-catenin signaling cooperate in suppression of chondrocyte differentiation in experimental models of FGFR signaling in cartilage
Biochimica et Biophysica Acta - Molecular Basis of Disease, rok: 2015, ročník: 1852, vydání: 5, DOI
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Instability restricts signaling of multiple fibroblast growth factors
Cellular and Molecular Life Sciences, rok: 2015, ročník: 72, vydání: 12, DOI
2014
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Effect of FGFR inhibitors on chicken limb development
Development Growth & Differentiation, rok: 2014, ročník: 56, vydání: 8, DOI
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The paradox of FGFR3 signaling in skeletal dysplasia: Why chondrocytes growth arrest while other cells over proliferate
Mutation Research - Reviews in Mutation Research, rok: 2014, ročník: 759, vydání: January–March, DOI
2013
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Expression of FGF19 in Human Embryonic Stem Cells
STEM CELLS, rok: 2013, ročník: 31, vydání: 11, DOI