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    Targeting the formyl peptide receptor 1 for treatment of glioblastoma

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    PhD Thesis (7.532Mb)
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    Publication date
    2021
    Author
    Ahmet, Djevdet S.
    Supervisor
    Afarinkia, Kamyar
    Shnyder, Steven D.
    Keyword
    Formyl peptide receptor 1
    Annexin-A1
    Glioblastoma
    Spheroid
    Drug discovery
    Synthetic medicinal chemistry
    Small molecule antagonists
    Rights
    Creative Commons License
    The University of Bradford theses are licenced under a Creative Commons Licence.
    Institution
    University of Bradford
    Department
    Faculty of Life Sciences
    Awarded
    2021
    
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    Abstract
    Background and Aims Gliomas account for over half of all primary brain tumours and have a very poor prognosis, with a median survival of less than two years. There is an urgent and unmet clinical need to develop new therapies against glioma. Recent reports have indicated the overexpression of FPR1 in gliomas particularly in high grade gliomas. The aim of this project was to identify and synthesise small molecule FPR1 antagonists, and to demonstrate a proof of principle in preclinical in vitro and in vivo models that small molecule FPR1 antagonism can retard expansion of glioma. Methods A number of small molecule FPR1 antagonists were identified by in silico design, or from the literature and then were prepared using chemical synthesis. FPR1 antagonists were evaluated in vitro for their ability to abrogate FPR1-induced cellular responses in a range of models including calcium mobilisation, cell migration, and invasion. The efficacy of FPR1 antagonist ICT12035 in vivo was assessed in a U-87 MG subcutaneous xenograft model. Results Virtual high throughput screening using a homology model of FPR1 led to the identification of two small molecule FPR1 antagonists. At the same time chemical synthesis of two other antagonists, ICT5100 and ICT12035 as well as their analogues were carried out. The FPR1 antagonists were assessed in calcium flux assay which gave an insight into their structure-activity relationship. Further investigation of both ICT5100 and ICT12035 demonstrated that both small molecule FPR1 antagonists were effective at abrogating FPR1-induced calcium mobilisation, migration, and invasion in U- 87 MG in vitro models in a dose-dependent manner. ICT12035 is a particularly selective and potent inhibitor of FPR1 with an IC50 of 37.7 nM in calcium flux assay. Additionally, it was shown that the FPR1 antagonist ICT12035 was able to arrest the growth rate of U-87 MG xenografted tumours in mice. Conclusion The results demonstrate that targeting FPR1 by a small molecule antagonist such as ICT12035, could provide a potential new therapy for the treatment of glioblastoma.
    URI
    http://hdl.handle.net/10454/19271
    Type
    Thesis
    Qualification name
    PhD
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