Chemical Biology and Early Stages of Drug Discovery

化学生物学和药物发现的早期阶段

• 批准号: RGPIN-2015-05529
• 负责人: Tsantrizos, Youla
• 金额: $ 3.28万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613605
• 关键词: Chemical; Biology; Early; Stages; Drug

A key objective of our research program is the design and synthesis of molecular tools that can be used to probe the therapeutic value of biological targets. A related objective is the optimization of hit and lead compounds into pre-clinical candidates. These efforts mandate the development of efficient synthetic protocols that are amenable to modular, high throughput preparation of structurally diverse compound libraries. Fundamental to our research is the implementation of structural tools to guide our medicinal chemistry efforts. This proposal describes three of our projects, focusing on the human enzymes: 1. farnesyl pyrophosphate synthase (hFPPS), 2. geranylgeranyl pyrophosphate synthase (hGGPPS), and 3. the zinc metalloproteinase ZMPSTE24. Human FPPS and GGPPS control the levels of human isoprenoids and the post-translational prenylation of all small GTPase proteins that are crucially important in cell signalling, cell proliferation and neuronal synaptic plasticity. Recently, we reported the discovery of novel pyridine-, thienopyrimidine- and indole-based inhibitors of hFPPS that bind to the active site and/or a catalytically relevant allosteric pocket of the enzyme. The design and synthesis of optimized hFPPS allosteric inhibitors will be one of the key topics in this proposal. Structural remodelling of these compounds will include conformational rigidification to mimic the enzyme-bound conformation, the asymmetric synthesis of a-aminophosphonic acids and the synthesis of cyclic phostones that are key pharmacophores for this target. In contrast to hFPPS (which is already a clinically validated biological target), little is known about the consequences of inhibiting selectively hGGPPS or ZMPSTE24 in vivo. Only few weak inhibitors of these enzymes are known and limited structural information on ligand/protein interactions have been reported. Our research projects aim to provide valuable insight into the role of these proteins in neurodegeneration (hGGPPS) and oncogenesis (ZMPSTE24). Statistic Canada has recently reported that 30% of all deaths amongst Canadians are due to cancer. Additionally, in 2010, the WHO estimated the prevalence of dementia to be 35.6 million worldwide and expected to increase to 65.7 million by 2030. Therefore, there is enormous need for the validation of new targets for the treatment of cancer and neurodegeneration. The main priority of our research is to provide molecular tools that can guide drug discovery efforts in these two important disease areas. Our studies are truly multidisciplinary and involve a seamless integration of synthetic organic chemistry, structural research and biochemistry. I believe that our program provides an excellent training ground for students and research fellows (HQPs) interested in pursuing an academic or industrial career in biomedical or pharmaceutical sciences.

我们研究计划的一个关键目标是设计和合成可用于探测生物靶标的治疗价值的分子工具，一个相关的目标是将命中化合物和先导化合物优化为临床前候选药物。适合结构多样化化合物库的模块化、高通量制备的高效合成方案的基础是实施结构工具来指导我们的药物化学工作，该提案描述了我们的三个项目，重点关注人类酶： 1.法尼基焦磷酸合酶（hFPPS），2.香叶基香叶基焦磷酸合酶（hGGPPS），和3.锌金属蛋白酶ZMPSTE24。 人类 FPPS 和 GGPPS 控制人类类异戊二烯的水平以及所有小 GTP 酶蛋白的翻译后异戊二烯化，这些蛋白对于细胞信号传导、细胞增殖和神经元突触可塑性至关重要。最近，我们报告了新型吡啶、噻吩并嘧啶和神经元突触可塑性的发现。基于吲哚的 hFPPS 抑制剂，与酶的活性位点和/或催化相关的变构袋结合。优化 hFPPS 变构抑制剂的合成将是该提案的关键主题之一。这些化合物的结构重塑将包括模拟酶结合构象的构象刚性化、α-氨基膦酸的不对称合成以及环状膦的合成。与 hFPPS（已经是临床验证的生物靶标）相比，选择性抑制 hGGPPS 或的后果知之甚少。 ZMPSTE24 体内的这些酶的弱抑制剂是已知的，并且已报道的配体/蛋白质相互作用的结构信息有限。我们的研究项目旨在为这些蛋白质在神经变性 (hGGPPS) 和肿瘤发生 (ZMPSTE24) 中的作用提供有价值的见解。 。 加拿大统计局最近报告称，加拿大人的死亡中有 30% 是由癌症造成的。此外，世界卫生组织在 2010 年估计全球痴呆症患病人数为 3560 万人，预计到 2030 年将增加到 6570 万人。需要验证治疗癌症和神经退行性疾病的新靶点 我们研究的主要重点是提供可以指导这两个重要疾病领域的药物发现工作的分子工具。 我们的研究是真正的多学科研究，涉及合成有机化学、结构研究和生物化学的无缝整合，我相信我们的项目为有兴趣在生物医学或制药领域从事学术或工业职业的学生和研究员 (HQP) 提供了一个极好的培训基地。科学。