A Chemistry Platform for Delivering Novel Small Molecule Therapies for Pancreatic Cancer

为胰腺癌提供新型小分子疗法的化学平台

• 批准号: 2475009
• 金额: --
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2475009
• 关键词: Chemistry; Platform; Delivering; Novel; Small

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.

胰腺癌 (PC) 是一种毁灭性的疾病，大多数患者在诊断后 6 个月内就会死亡。与大多数其他癌症不同，患者的预后在过去 30 年中几乎保持不变，包括免疫治疗。本申请旨在开发一种口服的肾上腺髓质素 (AM) 受体 AM2 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对PC的生长和发展具有重要作用。 Richards、Harrity 和 Tim Skerry 教授（肿瘤学/代谢系）发现了一系列强效化合物，在 PC 原位小鼠模型中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不可用于口服给药。然而，最近发现一个小的杂环片段 SHF-856 对 AM2 表现出有希望的抑制水平。这种化合物合成起来非常容易处理，类似于药物，并且易于模块化变化。所申请的资金是将这种先导化合物开发成用于治疗 PC 的口服化合物系列。旨在通过片段筛选识别新型 AM 受体拮抗剂的初步工作确定了一个小杂环片段 SHF-856，该片段显示出有希望的抑制水平。这是一个令人兴奋的先导化合物，因为它是一种低分子量的类药物化合物，适合类似物合成。研究计划：包括第一年要进行的实验的详细信息以及 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 2 和 3 年项目预期方向的总体概述。在前 12 个月内，学生将：重新合成当前的主要候选者，优化合成路线，重新测试 生物活性的初步筛选当前先导化合物的设计和合成类似物与分子建模师合作设计新化合物开发合成路线在初级测定中测试化合物在项目的其余部分中，此迭代设计过程将继续，直到我们获得具有所需特性（效力、物理化学特性）的化合物。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，还将在体内模型中进行测试。