Lead Optimization of Lapatinib Analogs for Human African Trypanosomiasis

治疗非洲人类锥虫病的拉帕替尼类似物的先导化合物优化

基本信息

批准号：
8904898
负责人：
KOJO A. MENSA-WILMOT
金额：
$ 67.25万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8904898
关键词：
Active Sites Acute Advocate Affect Affinity Chromatography African Trypanosomiasis Animals Back Binding Biochemistry Biological Biological Assay Biology Blood Circulation Cell physiology Cells Chemicals Chronic Clinic Clinical Disease Drug Kinetics Drug Targeting Endocytosis Eukaryota Genes Goals Health Human In Vitro Industry Infection Lead Measures Modeling Molecular Target Mus Neuraxis Parasitemia Parasites Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Phosphotransferases Plasma Preclinical Drug Evaluation Property Protein Kinase Protein Tyrosine Kinase Proteins Proteome Proteomics RNA Interference Safety Staging Structure Techniques Testing Therapeutic Toxic effect Transferrin Trypanosoma Trypanosoma brucei brucei Tyrosine Kinase Inhibitor Tyrosine Phosphorylation Tyrphostins Validation Work World Health analog cost design drug development drug discovery effective therapy human disease improved killings knock-down lapatinib mouse model neglect novel pre-clinical preclinical study programs prototype scaffold screening

项目摘要

DESCRIPTION (provided by applicant): New drugs are needed for treatment of the disease human African trypanosomiasis (HAT) that is caused by the protist Trypanosoma brucei. Protein tyrosine (Tyr) phosphorylation is important for regulating numerous cellular processes in eukaryotes, and inhibition of Tyr phosphorylation by protein Tyr kinases (PTKs) has yielded several well-tolerated drugs that are in clinical use. In trypanosomes, Tyr phosphorylation is understudied, and the Tyr phosphorylation pathway has not been exploited to produce new lead drugs. Our long-term project goals are to (i) employ phenotypic assays to discover chemical scaffolds that inhibit Tyr phosphorylation of trypanosome proteins; (ii) optimize the scaffolds for pharmacokinetic, and physicochemical properties while preserving selectivity in trypanocidal activity over host cells; (iii) identify targets that bind the optimized leads; and (iv) evaluate te best-performing optimized analogs in acute and chronic murine models of HAT. Towards these goals, we have performed a focused chemical screen of drugs directed against human Tyr kinases, and identified 7 hits that killed axenic bloodstream T. brucei at low micromolar concentrations. Subsequently, we tested three of the drugs in a mouse model of HAT and found that the human Tyr kinase inhibitor lapatinib (GlaxoSmithKline) controls the trypanosome infection and cures 25% of mice infected with the parasite; we therefore deemed lapatinib to be a "Lead" compound. We initiated a lead optimization program that has produced 7 novel compounds with nanomolar activity in phenotypic assays against bloodstream T. brucei. We will pivot on our discovery of NEU617 which has an effective concentration of 42 nanomolar, to continue our optimization of lapatinib analogs to achieve better pharmacokinetic, physicochemical and improved selectivity and toxicity profiles. Using lapatinib as the prototype, we have developed multiple approaches for identifying the targets of these potent novel leads, and we will apply these techniques to identify targets of our optimized leads, and to chemically and genetically validate targets of the potential drugs. The best compounds from these optimization studies will be evaluated for efficacy in murine models of HAT.

描述（由申请人提供）：需要新药来治疗由原生生物布氏锥虫引起的人类非洲锥虫病（HAT）。蛋白酪氨酸 (Tyr) 磷酸化对于调节真核生物中的众多细胞过程非常重要，通过蛋白 Tyr 激酶 (PTK) 抑制 Tyr 磷酸化已产生了几种临床使用的耐受性良好的药物。在锥虫中，Tyr 磷酸化尚未得到充分研究，并且 Tyr 磷酸化途径尚未被用来生产新的先导药物。我们的长期项目目标是 (i) 采用表型分析来发现抑制锥虫蛋白酪氨酸磷酸化的化学支架； (ii) 优化支架药代动力学和理化特性，同时保留对宿主细胞杀锥虫活性的选择性； (iii) 确定与优化的先导化合物结合的目标； (iv) 评估 HAT 急性和慢性小鼠模型中表现最佳的优化类似物。为了实现这些目标，我们对针对人类酪氨酸激酶的药物进行了集中的化学筛选，并确定了 7 种能够在低微摩尔浓度下杀死无菌血流布氏锥虫的药物。随后，我们在 HAT 小鼠模型中测试了这三种药物，发现人类酪氨酸激酶抑制剂拉帕替尼（葛兰素史克）控制了锥虫感染，并治愈了 25% 感染该寄生虫的小鼠；因此，我们认为拉帕替尼是“先导”化合物。我们启动了一项先导化合物优化计划，已生产出 7 种在针对血流 T. brucei 的表型测定中具有纳摩尔活性的新型化合物。我们将以 NEU617（有效浓度为 42 纳摩尔）的发现为基础，继续优化拉帕替尼类似物，以实现更好的药代动力学、物理化学以及改善的选择性和毒性特征。使用拉帕替尼作为原型，我们开发了多种方法来识别这些有效的新先导化合物的靶点，我们将应用这些技术来识别我们优化的先导化合物的靶点，并对潜在药物的靶点进行化学和遗传学验证。这些优化研究中的最佳化合物将在 HAT 小鼠模型中进行功效评估。