Optimization and Modes of Action of NEU-4438, a New Anti-trypanosome Lead Drug

摘要 需要具有与目前临床候选药物SCYX-7158不同作用模式的新药， 对由T.布氏杆菌从食品药品管理局开始- 批准的药物拉帕替尼（EC 50 = 1600 nM;选择性指数（SI）= 4（与人HepG 2细胞相比），我们 在药物化学活动中合成了超过540种类似物，重点是优化SI，毒性 概况、代谢、物理化学性质、水溶性（Aq. Sol.）和中枢神经系统恍惚。我们的新 NEU 4438是口服生物可利用的，并延长锥虫感染小鼠的生命2.4（P = 0.008; Kaplan- Meir分析），伴随着寄生虫血症减少109倍。喹啉亚胺，NEU-4438具有优异的 效价（GI 50：0.013 μM）、选择性（SI：>2000）、理化性质（aq.解决方案：880 μM; LogD 7.4：0.9; cLogP：2.52）和体外ADME（人PPB%：15; HLM克林特：21.8 µl/min/mg蛋白; RH克林特：13.1 µ//min/106 细胞）。如果NEU 4438失败，则可将6个NEU 4438相关高级命中作为可能的电极导线进行评估 在鼠模型中治愈HAT。我们将通过优化喹啉亚胺支架来进一步我们的工作 在构建虚拟库后使用单例和并行药物化学方法， 像毒品一样的预期化合物将通过漏斗进行合成和筛选， 选择具有最佳选择性指数、溶解性和物理化学性质的那些。高级点击将是 在小鼠中评估安全性、组织暴露和脑转移率，之后， 将在HAT小鼠模型中测试这些特征的功效，以选择先导药物（以NEU 4438为例）， 可能进展为临床前候选药物。识别药物电极导线NEU 4438-的靶点 将使用光亲和探针鉴定结合蛋白。同时，分子作用模式将是 研究了NEU 4438扰动锥虫蛋白质组，随后进行假设的检验， 从蛋白质组学数据中。为了鉴定生理靶点，敲低后观察到的表型 预期编码NEU 4438结合蛋白的基因的表达将“表型复制”加入NEU 4438的效果， T.布鲁塞。我们的成就使我们能够提供两种新的临床前候选药物，并确定其 生理目标以及下一个资助期的行动模式。

ABSTRACT New drugs with different modes of action than SCYX-7158, the current clinical candidate, are needed for chemotherapy of human African trypanosomiasis (HAT) caused by T. brucei spp. Starting with the FDA- approved drug lapatinib (EC50 = 1600 nM; selectivity index (SI) = 4 (compared to human HepG2 cells), we have synthesized over 540 analogs in a medicinal chemistry campaign focused on optimizing SI, toxicity profile, metabolism, physicochemical properties, aqueous solubility (Aq. Sol.) and CNS penetrance. Our new lead NEU4438 is orally bioavailable and extends the life of trypanosome-infected mice 2.4 (P = 0.008; Kaplan- Meir analysis), accompanied by a 109-fold reduction in parasitemia. A quinolinimine, NEU-4438 has excellent potency (GI50: 0.013 μM), selectivity (SI: >2000), physicochemical properties (aq. sol.: 880 μM; LogD7.4: 0.9; cLogP: 2.52) and in vitro ADME (human PPB%: 15; HLM Clint: 21.8 µl/min/mg protein; RH Clint: 13.1 µ//min/106 cells). Six NEU4438-related advanced hits are available for evaluation as possible leads, should NEU4438 fail to cure HAT in murine models of the disease. We will further our work by optimizing the quinolinimine scaffold using singleton and parallel medicinal chemistry approaches after constructing a virtual library, shaped by drug-like expectations in silico. Compounds will be synthesized and screened through a funnel established to select those with the best selectivity index, solubility, and physicochemical properties. Advanced hits will be evaluated in mice for safe safety, tissue exposure, and brain penetrance, after which those with the best features will be tested for efficacy in mice models of HAT to select lead drugs (exemplified by NEU4438), that may be progressed into preclinical candidates. Towards identification of the targets of the drug lead, NEU4438- binding proteins will be identified using photoaffinity probes. Concurrently, molecular modes of action will be studied by NEU4438 perturbation of the trypanosome proteome, followed by tests of hypotheses formulated from the proteomics data. In order to identify physiological targets, the phenotypes observed after knockdown of genes encoding NEU4438-binding proteins will be expected to “phenocopy” the effect of adding NEU4438 to T. brucei. Our achievements put us on track to deliver two new preclinical candidates, and to identify their physiological targets as well as modes of action in the next funding period.