Targeting S-adenosylmethionine decarboxylase for HAT drug discovery

描述（由申请方提供）：人类非洲锥虫病（HAT）由寄生原生动物布氏锥虫引起。HAT被列为世卫组织第1类疾病（新出现的和不受控制的），对非洲流行地区的健康和经济成本造成巨大负担。这种疾病是致命的，除非治疗和目前的治疗遭受高毒性和困难的治疗方案。此外，目前没有一种药物对该疾病的物种和阶段都有效。目前非常需要将最近在了解寄生虫基本生物学方面取得的进展转化为新的安全、有效的药物，这些药物对所有形式的寄生虫都有活性，而且易于服用。多胺是细胞生长所需的必需代谢物。多胺生物合成酶，包括鸟氨酸脱羧酶（ODC）和S-腺苷甲硫氨酸脱羧酶（S-adenosylmethionine decarboxylase，S-AdenosylMetDC）是寄生虫所必需的。α-二氟甲基鸟氨酸（DFMO）是一种ODC的自杀抑制剂，是治疗晚期T.冈比亚，验证多胺生物合成作为药物靶标的寄生虫。我们的团队系统地探索了多胺生物合成途径中其他酶的潜力，以验证新的抗锥虫药物的发现，从而验证了HAT MetDC作为HAT药物发现的非常有前途的靶标。我们证明了CD 3 MetDC对血液T阶段是必需的。利用遗传学方法研究了布鲁氏菌寄生虫，我们发现这种酶受到一种在哺乳动物细胞中没有发现的独特机制的调节。从先前鉴定的人β-MetDC抑制剂（MDL 73811）开始，我们鉴定了新的化合物（例如Genz 644131），其是T.在体外具有针对寄生虫的nM活性，并且在早期小鼠感染模型中具有治愈性。然而，Genz 644131对小鼠中的晚期感染模型无效。我们的目标是确定新的抑制剂T。布氏杆菌在MetDC中没有这种责任，并围绕这些抑制剂进行领先的优化计划，以确定具有治疗两个物种和两个阶段HAT的潜力的临床前候选药物。我们已经制定了一项由两部分组成的战略，该战略应最大限度地增加我们实现这一目标的机会。在目标1中，我们将对Genz 644131系列进行额外的先导化合物优化工作，目标是在后期模型中识别具有改善的脑渗透和活性的化合物。在目标2中，我们将进行高通量筛选（HTS），以确定新的T。布氏杆菌MetDC抑制剂。将对从HTS中鉴别的化合物进行验证，并根据靶标选择矩阵（包括效价、选择性、全细胞试验中的活性和适当的ADME特性）选择两个最佳系列。在目标3中，将执行顶级系列的迭代领先优化程序。在目标4中，将进行作用机制和耐药性研究，为确定的候选物的适用性提供支持数据。DNDi已同意担任该项目的项目顾问。 公共卫生相关性：人类非洲昏睡病（HAT）是一种致命的昆虫传播疾病，由寄生病原体引起，如果不治疗会导致死亡。目前的药物治疗具有高毒性，并且难以在该疾病流行的非洲农村环境中施用。该提案的目标是确定新型，安全和易于管理的化合物，在动物模型中治愈这种疾病的早期和晚期感染，从而在5年基金期结束时提名临床前开发候选药物用于治疗HAT。

DESCRIPTION (provided by applicant): Human African trypanosomiasis (HAT) is caused by the parasitic protozoan, Trypanosoma brucei. HAT is listed as a WHO Category 1 disease (emerging and uncontrolled) that exerts a large burden in both health and economic costs to the endemic regions in Africa. The disease is fatal unless treated and current therapies suffer from high toxicity and difficult treatment regimes. Furthermore none of the current drugs are effective against both species and stages of the disease. There is a great need to translate recent advances in the understanding of the basic biology of the parasite into new safe, effective drugs that have activity against all forms of the parasite, and which can be easily administered. Polyamines are essential metabolites that are required for cell growth. The polyamine biosynthetic enzymes, including ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC) are essential to the parasite. a-difluoromethyornithine (DFMO), a suicide inhibitor of ODC, is the frontline treatment for late-stage T. gambiense, validating polyamine biosynthesis as a drug target in the parasite. Our group has systematically explored the potential for other enzymes in the polyamine biosynthetic pathway to be validated for the discovery of new anti-trypanosomal agents, leading to the validation of AdoMetDC as a highly promising target for HAT drug discovery. We demonstrated that AdoMetDC is essential to blood stage T. brucei parasites using genetic approaches and we discovered that the enzyme is regulated by a unique mechanism not found in mammalian cells. Starting from a previously identified human AdoMetDC inhibitor (MDL 73811) we identified new compounds (eg Genz 644131) that are potent irreversible inhibitors of T. brucei AdoMetDC, with nM activity against parasites in vitro, and that are curative in early stage mouse infection models. Genz 644131 however is not effective against late stage infection models in mice. Our objectives are to identify novel inhibitors of T. brucei AdoMetDC without this liability, and to undertake a lead optimization program around these inhibitors to identify a preclinical candidate with the potential to treat both species and both stages of HAT. We have developed a two-part strategy that should maximize the chances that we can achieve this goal. In Aim 1 we will undertake additional lead optimization work on the Genz 644131 series with the goal of identifying compounds with improved brain penetration and activity in the late stage model. In Aim 2 we will conduct a high throughput screen (HTS) to identify novel T. brucei AdoMetDC inhibitors. Compounds identified from the HTS will be validated, and two of the best series will be selected based on a target selection matrix that includes potency, selectivity, activity in whole cell assays and suitable ADME properties. An iterative lead optimization program of the top series will be prosecuted in Aim 3. In Aim 4 mechanism of action and resistance studies will be undertaken, providing supporting data on suitability of the identified candidates. DNDi has agreed to serve as program consultants on this project. Public Health Relevance: Human African sleeping sickness (HAT) is a fatal insect borne disease caused by a parasitic pathogen that leads to death if untreated. Current drug therapies have high toxicity and are difficult to administer in rural African settings where the disease is endemic. The goal of this proposal is to identify novel, safe and easily administered compounds that cure both early and late stage infections of this disease in animal models, resulting in the nomination of a preclinical development candidate for the treatment of HAT by the completion of the 5-year fund period.