17 research outputs found
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Targeting the formyl peptide receptor 1 for treatment of glioblastoma
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
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Application of small molecule FPR1 antagonists in the treatment of cancers
YesThe formylpeptide receptor-1 (FPR1) is a member of the chemotactic GPCR-7TM formyl peptide receptor family, whose principle function is in trafficking of various leukocytes into sites of bacterial infection and inflammation. More recently, FPR1 has been shown to be expressed in different types of cancer and in this context, plays a significant role in their expansion, resistance and recurrence. ICT12035 is a selective and potent (30 nM in calcium mobilisation assay) small molecule FPR1 antagonist. Here, we demonstrate the efficacy of ICT12035, in a number of 2D and 3D proliferation and invasion in vitro assays and an in vivo model. Our results demonstrate that targeting FPR1 by a selective small molecule antagonist, such as ICT12035, can provide a new avenue for the treatment of cancers
Discovery and Computer Aided Potency Optimization of a Novel Class of Small Molecule CXCR4 Antagonists
<div><p>Amongst the chemokine signalling axes involved in cancer, chemokine CXCL12 acting on chemokine receptor CXCR4 is particularly significant since it orchestrates migration of cancer cells in a tissue-specific metastatic process. High CXCR4 tumour expression is associated with poor prognosis of lung, brain, CNS, blood and breast cancers. We have identified a new class of small molecule CXCR4 antagonists based on the use of computational modelling studies in concert with experimental determination of <i>in vitro</i> activity against CXCL12-induced intracellular calcium mobilisation, proliferation and chemotaxis. Molecular modelling proved to be a useful tool in rationalising our observed potencies, as well as informing the direction of the synthetic efforts aimed at producing more potent compounds.</p> </div
A view of the residues surrounding the binding pocket of CXCR4.
<p>A view of the residues surrounding the binding pocket of CXCR4.</p
Structures of TN14003, AMD3100, AMD3465, AMD11070, and GSK812397.
<p>Structures of TN14003, AMD3100, AMD3465, AMD11070, and GSK812397.</p
Effect of antagonists on CXCL12 induced migration of U87 cells in a two chamber assay.
<p>Effect of antagonists on CXCL12 induced migration of U87 cells in a two chamber assay.</p