Lead optimisation of a new radioprotector

拟议的项目是一个研究方案的一部分，该方案旨在开发一种新药，以减少癌症放射治疗的副作用。这些副作用是由对肿瘤附近正常组织的辐射损伤引起的。由于在许多情况下，处于风险中的正常组织可以局部应用（例如，乳腺癌患者中的皮肤、前列腺癌患者中的直肠粘膜、正在接受头颈部肿瘤治疗的所有患者中的口腔粘膜）。一种使细胞对X射线不太敏感的药物（这些药物被称为辐射防护剂）只是局部应用于有风险的正常组织。为此，我们开发了一种名为甲基丙胺的新辐射防护药物，其效力是以前开发的辐射防护剂的100倍。不幸的是，甲基丙胺不适合我们的目的，因为在较高的浓度下，它对某些细胞是有毒的。必须克服这一障碍，使项目对潜在的商业赞助者具有吸引力。我们的目标是通过去除引起细胞毒性的分子特征来修饰甲基丙胺。我们已经确定，这是可行的，通过合成和评估一个小家庭的甲基丙胺类似物。一些毒性较小的家庭成员已经被确定。有了这些知识，我们现在建议使用特殊的计算机程序来设计一个更大的家族的甲基丙胺类似物，并合成和测试每一个，以确定最有希望的候选人为我们的目的。一旦通过了疗效窗口期障碍，就可以在适当的赞助下解决商业化和临床实施的后续里程碑。一家澳大利亚公司已经表达了浓厚的兴趣，并正在评估这一机会。

The proposed project is part of a research programme aimed at developing a new drug to reduce the side effects of cancer radiotherapy. These side effects result from the radiation damage to normal tissues close to the tumour. Since in many instances the normal tissues at risk are accessible to topical application (eg. skin in breast cancer patients, rectal mucosa in prostate cancer patients, oral mucosa in all patients being treated for tumours in the head and neck region) the concept is very simple. A drug which makes cells less sensitive to X-rays (these drugs are called radioprotectors) is simply applied topically to the normal tissues at risk. For this purpose, we have developed a new radioprotecting drug called methylproamine which is 100-fold more potent than previously-developed radioprotectors. Unfortunately, methylproamine is not suitable for our purpose because at higher concentrations it is toxic to some cells. This hurdle must be overcome in order to make the project attractive to potential commercial sponsors. Our aim is to modify methylproamine by removing the molecular features that cause the cytotoxicity. We have established that this is feasible, by synthesising and evaluating a small family of methylproamine analogues. Some less toxic family members have already been identified. With this knowledge, we now propose to use special computer programmes to design a much larger family of methylproamine analogues, and to synthesise and test each one in order to identify the most promising candidate for our purpose. Once the efficacy window hurdle is passed, the subsequent milestones to commercialisation and clinical implementation can be addressed, with appropriate sponsorship. An Australian company has already expressed strong interest and is evaluating the opportunity.