A chemistry platform for delivering novel small molecule therapies for pancreatic cancer

胰腺癌（PC）是一种毁灭性的疾病，大多数患者在诊断后6个月内死亡。与大多数其他癌症不同，患者的预后在过去30年里几乎没有变化，包括免疫治疗。本应用旨在开发一种口服的肾上腺髓质素（AM）受体AM2的小分子拮抗剂，用于胰腺导管腺癌。越来越多的证据表明，AM在PC的生长发育中具有重要作用。Richards， harity和Tim Skerry教授（肿瘤学/代谢系）已经确定了一种有效的化合物系列，对原位PC小鼠模型具有令人印象深刻的功效（抑制肿瘤生长约80%）。该研究旨在开发一线静脉注射治疗，但我们目前的化合物系列无法用于口服给药。然而，最近发现一个小的杂环片段SHF-856在AM2中显示出有希望的抑制水平。这种化合物在合成上非常容易处理，像药物一样，并且可适应模块化变化。所要求的资金是将这种铅开发成可口服的用于治疗PC的化合物系列。

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.