Chemical Biology and Early Stages of Drug Discovery

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点治疗价值的分子工具。一个相关的目标是将命中和先导化合物优化为临床前候选物。这些努力要求开发有效的合成方案，其适合于结构多样的化合物文库的模块化、高通量制备。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。法呢基焦磷酸合成酶（hFPPS），2.香叶基香叶基焦磷酸合酶（hGGPPS），和3.锌金属蛋白酶ZMPSTE24。* 人FPPS和GGPPS控制人类异戊二烯的水平和所有小GT3蛋白的翻译后异戊烯化，其在细胞信号传导、细胞增殖和神经元突触可塑性中至关重要。最近，我们报道了新的吡啶，噻吩并嘧啶和吲哚为基础的抑制剂的hFPPS结合的活性位点和/或催化相关的变构口袋的酶的发现。优化hFPPS变构抑制剂的设计和合成将是本研究的重点课题之一。这些化合物的结构重塑将包括构象刚性化以模拟酶结合构象、α-氨基膦酸的不对称合成和作为该靶标的关键药效团的环状phostone的合成。与hFPPS（其已经是临床验证的生物靶标）相反，关于选择性抑制hGGPPS或ZMPSTE24在体内的后果知之甚少。只有少数弱抑制剂，这些酶是已知的和有限的配体/蛋白质相互作用的结构信息已被报道。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说，加拿大人30%的死亡是由于癌症。此外，2010年，世界卫生组织估计全世界痴呆症的患病率为3560万，预计到2030年将增加到6570万。因此，对于用于治疗癌症和神经变性的新靶点的验证存在巨大的需求。我们研究的主要优先事项是提供分子工具，可以指导这两个重要疾病领域的药物发现工作。我们的研究是真正的多学科，涉及合成有机化学，结构研究和生物化学的无缝集成。我相信，我们的计划为有兴趣在生物医学或制药科学领域从事学术或工业职业的学生和研究员（HQP）提供了一个很好的培训基地。

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.*********