scholarly journals Discovery of Novel Fibroblast Growth Factor Receptor 1 Kinase Inhibitors by Structure-Based Virtual Screening

2010 ◽  
Vol 53 (4) ◽  
pp. 1662-1672 ◽  
Author(s):  
Krishna P. Ravindranathan ◽  
Valsan Mandiyan ◽  
Anil R. Ekkati ◽  
Jae H. Bae ◽  
Joseph Schlessinger ◽  
...  
Keyword(s):  
Growth Factor ◽  
Virtual Screening ◽  
Fibroblast Growth Factor ◽  
Kinase Inhibitors ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth

scholarly journals Aryl extensions of thienopyrimidinones as fibroblast growth factor receptor 1 kinase inhibitors

2011 ◽  
Vol 52 (17) ◽  
pp. 2228-2231 ◽  
Author(s):  
Anil R. Ekkati ◽  
Valsan Mandiyan ◽  
Krishna P. Ravindranathan ◽  
Jae H. Bae ◽  
Joseph Schlessinger ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Kinase Inhibitors ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth

FGFR3 targeting strategies for achondroplasia

2012 ◽  
Vol 14 ◽  
Author(s):  
Melanie B. Laederich ◽  
William A. Horton
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Receptor Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Therapeutic Strategies ◽  
Signalling Pathways ◽  
Fibroblast Growth ◽  
Blocking Antibodies

Mutations that exaggerate signalling of the receptor tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) give rise to achondroplasia, the most common form of dwarfism in humans. Here we review the clinical features, genetic aspects and molecular pathogenesis of achondroplasia and examine several therapeutic strategies designed to target the mutant receptor or its signalling pathways, including the use of kinase inhibitors, blocking antibodies, physiologic antagonists, RNAi and chaperone inhibitors. We conclude by discussing the challenges of treating growth plate disorders in children.

Abstract 3640: Discovery of quinazolinones as fibroblast growth factor receptor (FGFR1-4) kinase inhibitors

2015 ◽  
Author(s):  
Olivier Querolle ◽  
Patrick Angibaud ◽  
Hélène Colombel ◽  
Virginie Caron ◽  
Isabelle Pilatte ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Kinase Inhibitors ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth

scholarly journals Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Ikuko Takeda Nakamura ◽  
Shinji Kohsaka ◽  
Masachika Ikegami ◽  
Hiroshi Ikeuchi ◽  
Toshihide Ueno ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Kinase Inhibitors ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Genetic Alterations ◽  
Functional Assay ◽  
Functional Evaluation ◽  
Fibroblast Growth ◽  
Wide Range

AbstractVarious genetic alterations of the fibroblast growth factor receptor (FGFR) family have been detected across a wide range of cancers. However, inhibition of FGFR signaling by kinase inhibitors demonstrated limited clinical effectiveness. Herein, we evaluated the transforming activity and sensitivity of 160 nonsynonymous FGFR mutations and ten fusion genes to seven FGFR tyrosine kinase inhibitors (TKI) using the mixed-all-nominated-in-one (MANO) method, a high-throughput functional assay. The oncogenicity of 71 mutants was newly discovered in this study. The FGFR TKIs showed anti-proliferative activities against the wild-type FGFRs and their fusions, while several hotspot mutants were relatively resistant to those TKIs. The drug sensitivities assessed with the MANO method were well concordant with those evaluated using in vitro and in vivo assays. Comprehensive analysis of published FGFR structures revealed a possible mechanism through which oncogenic FGFR mutations reduce sensitivity to TKIs. It was further revealed that recurrent compound mutations within FGFRs affect the transforming potential and TKI-sensitivity of corresponding kinases. In conclusion, our study suggests the importance of selecting suitable inhibitors against individual FGFR variants. Moreover, it reveals the necessity to develop next-generation FGFR inhibitors, which are effective against all oncogenic FGFR variants.

scholarly journals Fibroblast Growth Factor Receptor (FGFR) Signaling in GIST and Soft Tissue Sarcomas

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1533
Author(s):  
Andrea Napolitano ◽  
Alexandra E. Ostler ◽  
Robin L. Jones ◽  
Paul H. Huang
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Kinase Inhibitors ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Soft Tissue Sarcomas ◽  
Clinical Activity ◽  
Fibroblast Growth ◽  
Fgfr Signaling ◽  
Genetic Events

Sarcomas are a heterogeneous group of rare malignancies originating from mesenchymal tissues with limited therapeutic options. Recently, alterations in components of the fibroblast growth factor receptor (FGFR) signaling pathway have been identified in a range of different sarcoma subtypes, most notably gastrointestinal stromal tumors, rhabdomyosarcomas, and liposarcomas. These alterations include genetic events such as translocations, mutations, and amplifications as well as transcriptional overexpression. Targeting FGFR has therefore been proposed as a novel potential therapeutic approach, also in light of the clinical activity shown by multi-target tyrosine kinase inhibitors in specific subtypes of sarcomas. Despite promising preclinical evidence, thus far, clinical trials have enrolled very few sarcoma patients and the efficacy of selective FGFR inhibitors appears relatively low. Here, we review the known alterations of the FGFR pathway in sarcoma patients as well as the preclinical and clinical evidence for the use of FGFR inhibitors in these diseases. Finally, we discuss the possible reasons behind the current clinical data and highlight the need for biomarker stratification to select patients more likely to benefit from FGFR targeted therapies.

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