Lead Optimization of Lapatinib Analogs for Human African Trypanosomiasis

描述（由申请人提供）：需要新药来治疗由原生布鲁氏锥虫引起的非洲人类锥虫病。蛋白酪氨酸（Tyr）磷酸化对于调节真核生物的许多细胞过程很重要，通过蛋白酪氨酸激酶（PTKs）抑制Tyr磷酸化已经产生了几种耐受性良好的药物，并已在临床使用。在锥虫中，对Tyr磷酸化的研究尚不充分，Tyr磷酸化途径尚未被用于生产新的先导药物。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Tyr磷酸化的化学支架；（ii）优化支架

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.