Synthesis, Computational Modeling and Biological Evaluation of FPR-1 Antagonists

FPR-1(Formyl peptide receptor-1), a member of the 7TM GPCR superfamily, plays a key role in cell host defence and immune response. FPR-1 is activated by ANX-A1 and short-chain formyl peptides such as fMLF, both of which are produced by necrotic cells. FPR-1 activation upregulates cellular signalling pathways, leading to chemotaxis, angiogenesis, and cell survival. Over expression of FPR-1 has been observed in highly malignant (grade III and IV) astrocytic brain tumours. It is hypothesised that this overexpression combined with the necrotic and hypoxic nature of the tumour microenvironment promotes cell proliferation, angiogenesis, and the infiltrative nature of tumours. A small molecule antagonist of FPR-1, ICT12035, has been synthesised at the Institute of Cancer Therapeutics, demonstrating exceptional potency with an IC50 of 34 nM in U87MG Glioblastoma cell lines and in vivo efficacy in a subcutaneous model. The aim of the project is to synthesise novel analogues of the ICT12035 with more favourable physiochemical properties, such as modifying the lipophilicity of the molecule making it more CNS penetrant, while maintaining its potency. Structural analysis and docking studies were performed using computational software and key residues were identified at the binding pocket. six compounds, 21, 22, 23, 24, 26 and 32 were synthesised and tested for toxicity using MTT assay and a functional Ca2+ mobilisation assay was performed to establish their potency. All synthesised compounds are not toxic with the exception of (21) at 100µM. Both (21) and (23) demonstrated promising potencies with IC50 values of 75 nM and 20 nM respectively.

URI

https://bradscholars.brad.ac.uk/handle/10454/20576

Type

Thesis

Qualification name

PhD