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，大多数患者在确诊后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。该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，用于治疗胰腺导管腺癌。越来越多的证据表明AM在PC的生长和发展中起着重要的作用。理查德·哈里提和蒂姆·斯凯里教授(系)肿瘤学/新陈代谢)已经确定了一系列有效的化合物，在PC的原位小鼠模型中具有令人印象深刻的效果(抑制肿瘤生长约80%)。这项研究旨在开发一线静脉治疗，但我们目前的化合物系列不能用于口服。然而，最近，一个小的杂环片段SHF-856被发现在AM2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，类似药物，并且易于模数变化。申请的资金是将这种铅开发成一种口服可用化合物系列，用于治疗前列腺癌。

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.