The Development of novel antagonists of the calcitonin-like receptor/receptor activity modifying protein-3 adrenomedullin 2 receptor for the treatment of pancreatic cancer

This proposal is to identify small molecule drug candidates for treatment of pancreatic cancer. The hormone adrenomedullin (AM) has physiological functions and roles in tumorigenesis in pancreatic and other cancers. Two cell-surface receptors for AM exist: one fulfils predominantly physiological functions (AM1R) and one functions in disease (AM2R). Proof-of-concept studies show that 1) AM2Rs are expressed in almost all human pancreatic tumours, 2) antibody blockade of AM2Rs in mice has no gross effect but inhibits human pancreatic xenograft development, 3) gene knockout of the AM2R is phenotypically silent, but inhibits orthotopic tumour metastasis. We will use rational design starting from our lead compounds to identify novel AM2R antagonists. We will synthesise and test new compounds in screens for activity against AM-induced cAMP elevations. Agents will be counter-screened for selectivity against AM1R and related receptors before analysis of binding and efficacy, and assessment in pancreatic cell models in vitro and in vivo. Milestones: 1) 14 months, developable AM2R antagonists with Ki<250nM and 30-fold selectivity, 2) 24 months, lead series with Ki<10nM, 100-fold selectivity and appropriate pharmacokinetics for in vivo studies, 3) 30 months, functional well-tolerated compounds able to inhibit tumour growth (>70%) in vivo with and without concurrent gemcitabine treatment.