Lead Optimization of DHODH Inhibitors for Malaria

项目摘要。疟疾威胁着世界50%的人口，造成近60万人死亡 每年死亡人数最多的是非洲的五岁以下儿童。虽然一大批抗疟疾药物 已经被用来对抗这种疾病，耐药性已经损害了大多数临床上的有效性 批准的药物，以及最近对当前一线青蒿素的耐药性等位基因的鉴定 非洲的这种组合威胁着当前的疾病控制计划。因此，识别新药以 抗击抗药性疟疾对于继续抗击该疾病至关重要。我们的小组在 与疟疾风险药物公司(MMV)合作验证二氢罗酸脱氢酶是一种临床应用 通过对三唑嘧啶DSM265的研究，为治疗疟疾提供了有价值的药物靶点 在该项目因发现非靶标毒性而停止之前，已进入第二阶段临床开发 在临床前物种中。在目前的提案中，我们正在努力通过以下方式确定新一代DHODH抑制剂 专注于与DSM265不同的化学系列，因此预计不会有重叠的毒性曲线。 其次，我们计划基于结构的方法来识别将降低耐药性风险的抑制剂。 相比之下，DSM265在II期研究中选择了2名患者进行耐药性治疗。在目标一号中，我们 计划完成三个相关的基于吡唑的DHODH抑制剂系列的领导优化，由 使用计算方法的脚手架跳跃(与薛定谔合作)，来自于 在本基金期间完成的工作。我们的吡唑系列化合物已经证明 高效(亚纳摩尔到低微摩尔)，并降低了在 体外培养。我们对香港特别行政区有深入的了解，包括潜力驱动因素，以及 代谢热点，我们计划混合和匹配化学以确定具有改善代谢的化合物 稳定性将支持人体半衰期(&gt；100小时)和MMV设定的剂量目标(&lt；500毫克)。在AIMS 2中 3我们使用实验和计算相结合的方法(薛定谔)来定义 酶：与降低抗药性风险相关的配体动力学和热力学结合特性， 以及将抗性风险与化合物的物理化学性质相关联。计算模型和 测量的热力学/动力学参数将指导新化合物的设计和合成，预计 已经降低了耐药性风险。DHODH程序非常适合于研究绑定的贡献 能量学对耐药性的倾向，因为我们有三种不同化学物质的丰富结构信息 具有不同物理化学性质和对酶活性部位具有不同结合方式的系列。 成功完成这些目标将使确定最强大的DHODH候选者 临床开发，它将提供关键的学习如何在基于靶的药物中导航耐药性问题 针对一般增殖性疾病的药物发现计划，增加了我们研究的影响。

Project Summary. Malaria puts at risk 50% of the world’s population and is responsible for nearly 600,000 yearly deaths, mostly in children under the age of five in Africa. While a large portfolio of anti-malarial agents has been used to combat the disease, drug resistance has compromised the effectiveness of most clinically approved drugs, and the recent identification of resistance alleles against the current front line artemisinin combinations in Africa threatens current disease control programs. Thus, the identification of new drugs to combat drug resistant malaria is essential to continued progress against the disease. Our group in collaboration with Medicines for Malaria Venture (MMV) validated dihydroorotate dehydrogenase as a clinically valuable drug target for the treatment of malaria through studies on triazolopyrimidine DSM265, which advanced to phase II clinical development before the project was stopped due to discovery of off-target toxicity in preclinical species. In this current proposal we are working to identify new generation DHODH inhibitors by focusing on a different chemical series from DSM265, thus not expected to share an overlapping toxicity profile. Secondly, we plan structure-based approaches to identify inhibitors that will have reduced resistance risk compared to DSM265, which selected for resistance in 2 patients treated in the Phase II study. In aim one we plan to complete lead optimization of three related pyrazole-based DHODH inhibitor series, identified by scaffold hop using computational approaches (in collaboration with Schrödinger) from a pyrrole series we completed work on during the current fund period. Compounds from our pyrazole series have demonstrated high potency (sub nanomolar to low micromolar), and a reduced propensity to select for resistant parasites in vitro. We have a strong understanding of the SAR around these series, including the potency drivers, and the metabolic hot spots, and we plan mix and match chemistry to identify compounds with improved metabolic stability that will support human half-life (>100 h) and dosing targets (< 500 mg) set out by MMV. In aims 2 and 3 we use a combination of experimental and computational approaches (Schrödinger) to define the enzyme:ligand kinetic and thermodynamic binding properties that are associated with reduced resistance risk, as well as to correlate resistance risk to compound physical chemical properties. Computational models and measured thermodynamic/kinetic parameters will inform design and synthesis of new compounds predicted to have reduced resistance risk. The DHODH program is ideally suited to study the contribution of binding energetics to resistance propensity, as we have a wealth of structural information over three different chemical series with different physical chemical properties and alternative binding modes to the enzyme active site. Successful completion of these aims will allow identification of the strongest DHODH candidate for further clinical development, and it will provide key learnings on how to navigate resistance issues in target-based drug discovery programs for proliferative diseases in general, increasing the impact of our studies.