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。初步工作旨在通过片段筛选鉴定新的AM受体拮抗剂，鉴定出一个小的杂环片段SHF-856，显示出有希望的抑制水平。这是一个令人兴奋的线索，因为它是一种低分子量的类似药物的化合物，可以进行类似物合成。研究计划：包括第一年要进行的实验细节，6个月和12个月的预期可交付成果清单，以及第2年和第3年项目预期方向的总体大纲（如果预计获得博士学位）。在最初的12个月里，学生将：重新合成目前的候选先导药物；优化合成路线；在生物活性的初级筛选中重新测试当前先导药物的生物活性设计和合成类似物；与分子建模师一起设计新化合物；开发合成路线；在初级分析中测试化合物；在项目的其余时间里，这种迭代设计过程将继续，直到我们获得具有所需性质（效力，物理化学性质）的化合物。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，将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.