Targeting S-adenosylmethionine decarboxylase for HAT drug discovery

靶向 S-腺苷甲硫氨酸脱羧酶用于 HAT 药物发现

• 批准号: 8522134
• 负责人: Margaret A. Phillips
• 金额: $ 80.27万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8522134
• 关键词: Action Potentials; Adenosylmethionine Decarboxylase; Africa; African; African Trypanosomiasis; Anabolism; Animal Model; Area; Biological Assay; Biology; Blood; Blood - brain barrier anatomy; Brain; Categories; Cations; Cells; Cessation of life; Chemicals; Clinical; Consultations; Coupled; Data; Development; Disease; Dose; Drug Kinetics; Drug Targeting; Drug resistance; Eflornithine; Enzymes; Evaluation; Funding; Genetic; Goals; Health Care Costs; Housing; Human; In Vitro; Infection; Insecta; Ion Channel; Ion Transport; Lead; Libraries; Mammalian Cell; Metabolic; Modeling; Molecular Conformation; Molecular Profiling; Mus; Ornithine Decarboxylase; Ornithine Decarboxylase Inhibitor; Parasites; Pathway interactions; Pattern; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Polyamines; Property; Protocols documentation; Resistance; Rodent; Rural; Safety; Series; Staging; Surface; Testing; Toxic effect; Toxicology; Translating; Treatment Failure; Trypanosoma brucei brucei; Tumor stage; Validation; Work; analog; base; cell growth; chemical synthesis; chemotherapy; decarboxylase inhibitor; disorder risk; drug discovery; economic cost; enzyme pathway; high throughput screening; improved; in vivo; inhibitor/antagonist; lipophilicity; meetings; mouse model; novel; pathogen; pre-clinical; programs; public health relevance; receptor; resistant strain; response; screening; small molecule; suicide inhibitor

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.

描述(申请人提供)：人类非洲锥虫病(HAT)是由寄生原虫布鲁氏锥虫引起的。HAT被列为世卫组织第1类疾病(新发和失控)，对非洲流行地区的卫生和经济成本造成巨大负担。这种疾病除非得到治疗，否则是致命的，而目前的治疗方法存在高毒性和难以治疗的问题。此外，目前的药物没有一种对疾病的种类和阶段都有效。迫切需要将了解寄生虫基本生物学方面的最新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，而且很容易给药。多胺是细胞生长所必需的代谢物。多胺生物合成酶包括鸟氨酸脱羧酶和S腺苷蛋氨酸脱羧酶是寄生虫的必需酶。α-二氟甲基鸟氨酸(DFMO)是一种ODC的自杀抑制剂，是治疗晚期冈比亚毛滴虫的一线药物，证实了多胺生物合成是该寄生虫的药物靶标。我们的团队系统地探索了多胺生物合成途径中的其他酶被验证为发现新的抗锥虫药物的潜力，导致ADOMetDC被验证为HAT药物发现的一个非常有希望的目标。我们使用遗传学方法证明了ADOMetDC对于布鲁氏毛滴虫血液分期是必不可少的，并且我们发现该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。从一种已确定的人类ADOMetDC抑制剂(MDL 73811)开始，我们鉴定了新的化合物(例如Genz 644131)，这些化合物对布氏毛滴虫具有不可逆的抑制作用，在体外对寄生虫具有NM活性，并且对小鼠早期感染模型有疗效。然而，GENZ 644131对小鼠的晚期感染模型无效。我们的目标是寻找没有这种可能性的新型布氏支原体ADO-MetDC抑制剂，并围绕这些抑制剂开展一项领先的优化计划，以确定具有治疗HAT两种类型和两个阶段的潜力的临床前候选药物。我们已经制定了一个分两部分的战略，应该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系列进行额外的铅优化工作，目标是在后期模型中识别具有更好的大脑渗透率和活性的化合物。在目标2中，我们将进行高通量筛选(HTS)以确定新的布氏锥虫ADO-MetDC抑制剂。将对HTS确定的化合物进行验证，并根据目标选择矩阵选择最佳系列中的两个，目标选择矩阵包括效力、选择性、全细胞分析活性和合适的ADME特性。在目标3中，将执行顶级系列的迭代领导优化方案。在目标4中，将进行作用机制和阻力研究，提供关于已确定候选人的适宜性的支持性数据。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，由一种寄生性病原体引起，如果不治疗会导致死亡。目前的药物疗法毒性很高，很难在疾病流行的非洲农村地区实施。这项建议的目标是确定新的、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一名治疗HAT的临床前开发候选人。