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。所要求的资金是将这种先导化合物开发成治疗前列腺癌的口服化合物系列。旨在通过片段筛选识别新的AM受体拮抗剂的初步工作确定了一种显示出有希望的抑制水平的小杂环片段SHF-856。这是一个令人兴奋的线索，因为它是一种低分子质量的类药物化合物，可以进行模拟合成。研究计划：包括第一年进行的实验的细节和6和12个月的预期交付成果清单，以及如果预期获得博士学位，第二年和第三年的预期项目方向的大致大纲。在前12个月中，学生将：重新合成当前的领先候选者优化合成路线在当前领先化合物的生物活性设计和合成类似物的初级筛选中重新测试当前领先化合物的生物活性设计和合成类似物与分子建模人员合作设计新的化合物开发合成路线在项目的其余部分在初步分析中测试化合物迭代设计过程将继续，直到我们获得具有所需性质的化合物(效价，物理化学特性)。然后，这些化合物将在体外癌细胞模型中进行测试，如果可能的话，然后在体内模型中进行测试。

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.