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: 8141272
• 负责人: Margaret A. Phillips
• 金额: $ 83.35万
• 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/8141272
• 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 Delivery Systems; Drug Kinetics; 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; Screening procedure; 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; 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（由申请人提供）：人类非洲锥虫病（HAT）是由寄生原生动物布氏锥虫引起的。 HAT 被列为世界卫生组织 1 类疾病（新发且不受控制），给非洲流行地区带来巨大的健康和经济负担。除非得到治疗，否则这种疾病是致命的，并且目前的疗法具有高毒性和困难的治疗方案。此外，目前的药物没有一种对疾病的物种和阶段都有效。非常需要将寄生虫基本生物学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具有活性，并且易于施用。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（AdoMetDC）对于寄生虫至关重要。 a-二氟甲基鸟氨酸 (DFMO) 是 ODC 的自杀抑制剂，是晚期冈比亚毛虫的一线治疗方法，验证了多胺生物合成作为寄生虫的药物靶点。我们的小组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 AdoMetDC 作为 HAT 药物发现的一个非常有前途的靶点。我们利用遗传方法证明了 AdoMetDC 对于血期布氏锥虫寄生虫至关重要，并且我们发现该酶受到哺乳动物细胞中未发现的独特机制的调节。从先前鉴定的人类 AdoMetDC 抑制剂 (MDL 73811) 开始，我们鉴定了新化合物（例如 Genz 644131），它们是 T. brucei AdoMetDC 的有效不可逆抑制剂，在体外具有 nM 抗寄生虫活性，并且在早期小鼠感染模型中具有治疗作用。然而，Genz 644131 对小鼠晚期感染模型无效。我们的目标是确定没有这种责任的 T. brucei AdoMetDC 新型抑制剂，并围绕这些抑制剂进行先导优化计划，以确定有潜力治疗两个物种和 HAT 两个阶段的临床前候选药物。我们制定了一个由两部分组成的战略，应该最大限度地提高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，目标是识别在后期模型中具有改善的大脑渗透性和活性的化合物。在目标 2 中，我们将进行高通量筛选 (HTS)，以鉴定新型 T. brucei AdoMetDC 抑制剂。从 HTS 中鉴定出的化合物将得到验证，并且将根据目标选择矩阵选择两个最佳系列，其中包括效力、选择性、全细胞测定中的活性以及合适的 ADME 特性。顶级系列的迭代先导优化计划将在目标 3 中进行。在目标 4 中，将进行作用机制和耐药性研究，提供有关已确定候选人的适用性的支持数据。 DNDi 已同意担任该项目的项目顾问。 公共卫生相关性：非洲人类昏睡病 (HAT) 是一种致命的昆虫传播疾病，由寄生病原体引起，如果不及时治疗会导致死亡。目前的药物疗法具有高毒性，并且难以在该疾病流行的非洲农村地区实施。该提案的目标是确定新型、安全且易于给药的化合物，在动物模型中治愈该疾病的早期和晚期感染，从而在 5 年基金期结束时提名用于治疗 HAT 的临床前开发候选药物。