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

摘要 需要与目前临床候选药物SCYX-7158不同作用模式的新药 布氏锥虫引起的人非洲锥虫病的化疗。从FDA开始- 批准的药物拉帕替尼(EC50=1600 NM；选择性指数(SI)=4(与人HepG2细胞相比)，我们 在一个专注于优化SI毒性的药物化学活动中合成了540多个类似物 概况，代谢，物理化学性质，水的溶解度(AQ。Sol.)和中枢神经系统的穿透性。我们的新产品 铅NEU4438具有口服生物利用度，可延长锥虫感染小鼠的寿命2.4%(P=0.008；卡普兰- 梅尔分析)，伴随着寄生虫血症减少109倍。一种喹诺林亚胺，neu-4438具有极好的 效价(GI50：0.013μM)、选择性(SI：&gt；2000)、物理化学性质(AQ.Sol：880μM；LogD7.4：0.9； CLogP：2.52)和体外ADME(人PPB%：15；HLm基因：21.8微米L/分钟/毫克蛋白；RH基因：13.1微/分/毫克蛋白 单元格)。如果NEU4438失败，可将六个与NEU4438相关的高级命中作为可能的线索进行评估 在这种疾病的小鼠模型中治愈HAT。我们将通过优化喹诺亚胺支架来进一步推进我们的工作 在构建虚拟图书馆后使用单例和并行药物化学方法，由 在硅胶中的药物般的期望。化合物将通过建立的漏斗进行合成和筛选 选择那些具有最佳选择性指数、溶解度和物理化学特性的化合物。高级点击率将是 在小鼠身上进行安全安全性、组织暴露和脑透过率的评估，在此之后，那些拥有最好 这些特征将在HAT小鼠模型中进行有效性测试，以选择先导药物(如NEU4438)，即 可能会进展为临床前候选者。关于识别药物铅NEU4438的目标- 结合蛋白将使用光亲和探针进行鉴定。同时，分子作用模式将是 NEU4438研究了锥虫蛋白质组的扰动，随后对所提出的假设进行了检验 从蛋白质组学数据中。为了确定生理指标，基因敲除后观察到的表型 在编码NEU4438结合蛋白的基因中，有望将NEU4438添加到 布氏毛虫T.brucei我们的成就使我们走上了正轨，交付了两个新的临床前候选人，并确定了他们的 下一个供资期间的生理目标和行动模式。

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.