Identification of mlm receptor antagonists for treatment of cancer

Summary

Recent high impact publications have identified antagonism of the mlm receptor as a possible target for treatment of cancer. The native ligand of the receptor has been linked to cell proliferation which has been proven to be as a result of increased nitric oxide (NO) concentration. Studies have shown that NO induces components of PKC/ERK/AP-1 signalling pathways whereby PKC stimulates activity of the mitogen activated protein kinase. This triggers a phosphorylation cascade which has been linked to the activation of genes responsible for cell differentiation and proliferation. The development of antagonists for mlm thus limiting NO concentration is therefore key to the development of cancer therapeutics. No small molecule antagonists of the mlm receptor have been reported in the literature.

Our strategy will be to identify antagonists by consideration of the structures of antagonists of the closely related receptors. A database of antagonists will be generated and compounds modelled at the mlm receptor. Favoured compounds will then be synthesised and screened in the panel of mlm antagonist assays. Hits will be engineered for selectivity for the mlm receptor by comparative molecular modelling using both the mlm and structurally homologous receptors.

This studentship will aim to achieve the following objectives:

• to identify novel mlm antagonists as starting points for the development of novel therapeutics
• to optimise the compounds through medicinal chemistry approaches for drug-likeness and pharmaceutical and pharmacokinetic properties consistent with a bioavailable agent
• to generate selective agents (over antagonism of other receptors)
• to validate the origin of antagonism versus agonism on binding to the receptor
• to investigate high-throughput fragment screening as a tool to support the objectives of the project
• to work with our collaborators in support of the biological screening objectives of the project

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