A Chemistry Platform for Delivering Novel Small Molecule Therapies for Pancreatic Cancer

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Pancreatic cancer (PC) is a devastating disease that kills most patients within 6 months of diagnosis. Unlike most other cancers, the prognosis for patients has remained almost unchanged over the last 30 years, including immunotherapy. This application aims to develop an orally available small molecule antagonist of the adrenomedullin (AM) receptor AM2 for pancreatic ductal adenocarcinomas. Accumulating evidence has shown that AM has important actions in the growth and development of PC. Richards, Harrity & Prof Tim Skerry (Dept. Oncology/Metabolism) have identified a potent compound series with impressive efficacy in orthotopic mouse models of PC (inhibiting tumour growth by c.80%). That research is directed towards the development of a first-line intravenous treatment, but our current compound series is not available for oral administration. More recently however, a small heterocyclic fragment SHF-856 was found to show promising levels of inhibition at AM2. This compound is synthetically very tractable, drug-like and amenable to modular variation. The requested funding is to develop this lead into an orally available compound series for the treatment of PC.Preliminary work aimed at identifying novel AM receptor antagonists through fragment screening identified a small heterocyclic fragment SHF-856 that showed promising levels of inhibition. This is an exciting lead as it is a low molecular weight drug-like compound that is amenable to analogue synthesis.Research Plan: Including detail of experiments to be undertaken in the first year and a list of expected deliverables at 6 and 12 months plus a general outline of expected direction of project in years 2 and 3 if a PhD is anticipated.During the first 12 months the student will:Re-synthesise current lead candidateOptimise synthesis routesRe-test in primary screen for biological activity Design and synthesis analogues of the current leadWork with molecular modelers to design new compoundsDevelop synthetic routesTest compounds in primary assayDuring the rest of the project this iterative design process will continue until we obtain compounds with desired properties (potency, phys chem properties). These compound will then be test in in-vitro cancer cell models and then if possible in vivo models.