Chemical Biology and Early Stages of Drug Discovery

我们研究项目的一个关键目标是设计和合成可用于探测生物靶点治疗价值的分子工具。一个相关的目标是优化hit和先导化合物进入临床前候选药物。这些努力要求开发高效的合成协议，以适应模块化，高通量制备结构多样的化合物库。我们研究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，重点是人类酶：1。法尼基焦磷酸合成酶（hFPPS）；香叶基香叶基焦磷酸合成酶（hGGPPS）；锌金属蛋白酶ZMPSTE24。

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.