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

基本信息

批准号：
7983268
负责人：
Margaret A. Phillips
金额：
$ 82.93万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/7983268
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 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 disorder risk drug discovery economic cost enzyme pathway health economics 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

项目摘要

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）是由寄生虫原生动物Brucei引起的。 HAT被列为WHO 1类疾病（新兴和不受控制），对非洲流行地区的健康和经济成本造成了很大的负担。除非经过治疗和当前疗法患有高毒性和困难的治疗方案，否则该疾病是致命的。此外，目前的药物均未对疾病的物种和阶段有效。迫切需要将对寄生虫的基本生物学理解的最新进展转化为具有针对所有形式的寄生虫活性的新的安全，有效的药物，并且可以轻松进行。多胺是细胞生长所需的必需代谢产物。多胺生物合成酶，包括鸟氨酸脱羧酶（ODC）和S-腺苷甲硫代氨基氨酸脱羧酶（ADOMETDC）对于寄生虫至关重要。 A-二氟甲氨酸（DFMO）是ODC的自杀抑制剂，是晚期T. gambiense的前线处理，验证了多胺生物合成作为寄生虫中的药物靶标。我们的小组已系统地探索了多胺生物合成途径中其他酶的潜力，以发现新的抗牙龈剂，从而验证ADOMETDC作为HAT药物发现的高度有希望的目标。我们证明了AdometDC使用遗传方法对血液T. brucei寄生虫至关重要，我们发现该酶受哺乳动物细胞中未发现的独特机制调节。从先前鉴定的人AdometDC抑制剂（MDL 73811）开始，我们确定了新化合物（例如GENZ 644131），它们是Brucei AdometDC的有效不可逆抑制剂，具有NM的NM活性，在体外对寄生虫具有针对寄生虫的活性，并且在早期阶段小鼠感染模型中是治愈性的。 Genz 644131然而，针对小鼠的后期感染模型无效。我们的目标是在不承担此责任的情况下确定新的Brucei AdometDC抑制剂，并围绕这些抑制剂进行铅优化程序，以鉴定具有治疗这两个物种和两个hat阶段的临床前候选者。我们已经制定了一个分为两部分的策略，该策略应最大程度地提高我们可以实现这一目标的机会。在AIM 1中，我们将在Genz 644131系列上进行其他铅优化工作，目的是鉴定具有改善脑穿透和活性在晚期模型中的化合物。在AIM 2中，我们将进行高吞吐量屏幕（HTS），以识别新型的Brucei AdometDC抑制剂。从HTS确定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，该矩阵包括效力，选择性，全细胞测定中的活动和合适的ADME属性。顶级系列的迭代铅优化计划将在AIM 3中起诉。在AIM 4行动机制和抵抗研究机制中，将提供有关已确定候选者适用性的支持数据。 DNDI已同意担任该项目的计划顾问。公共卫生相关性：人类非洲熟睡（HAT）是一种致命的昆虫疾病，由寄生病原体引起的疾病，如果未治疗，会导致死亡。当前的药物疗法具有较高的毒性，并且在该疾病的非洲农村环境中难以给药。该提案的目的是确定新颖，安全且易于施用的化合物，可在动物模型中治愈该疾病的早期和晚期感染，从而提名临床前开发候选候选者，以通过完成5年基金时期来治疗HAT。