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.Yorkshire Cancer Researc
