Lead Optimization of Lapatinib Analogs for Human African Trypanosomiasis

描述（由申请人提供）：需要新的药物来治疗由原生动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许多细胞过程是重要的，并且通过蛋白酪氨酸激酶（PTK）抑制Tyr磷酸化已经产生了几种临床使用的耐受性良好的药物。在锥虫中，Tyr磷酸化研究不足，并且Tyr磷酸化途径尚未被利用来产生新的先导药物。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Tyr磷酸化的化学支架;（ii）优化支架， 这些方法包括：（i）鉴定药物代谢动力学和物理化学性质，同时保持对宿主细胞的杀锥虫活性的选择性;（iii）鉴定结合优化的先导物的靶标;和（iv）在HAT的急性和慢性鼠模型中评价表现最佳的优化类似物。为了实现这些目标，我们已经进行了针对人类Tyr激酶的药物的集中化学筛选，并确定了7种杀死纯血T。在低微摩尔浓度下的布氏杆菌。随后，我们在HAT小鼠模型中测试了三种药物，发现人酪氨酸激酶抑制剂拉帕替尼（葛兰素史克）控制锥虫感染，治愈了25%感染寄生虫的小鼠;因此，我们认为拉帕替尼是一种“先导”化合物。我们启动了一项先导优化计划，在针对血流T的表型测定中产生了7种具有纳摩尔活性的新型化合物。布鲁塞。我们将以发现有效浓度为42纳摩尔的NEU 617为重点，继续优化拉帕替尼类似物，以实现更好的药代动力学，物理化学和改善的选择性和毒性特征。使用拉帕替尼作为原型，我们已经开发了多种方法来识别这些有效的新型先导化合物的靶点，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验证。将在HAT鼠模型中评价来自这些优化研究的最佳化合物的疗效。

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.