Hit-to-lead optimization for sleeping sickness drug discovery

昏睡病药物发现的命中先导优化

• 批准号: 9751174
• 负责人: KOJO A. MENSA-WILMOT
• 金额: $ 69.08万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-19 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751174
• 关键词: Affinity Chromatography; African Trypanosomiasis; Awareness; Bioinformatics; Blood Circulation; Brain; Cells; Central Nervous System Infections; Chemicals; Classification; Disease Management; Dose; Drug Industry; Drug Kinetics; Economics; Excretory function; Eye; FDA approved; Funding; Genetic; Genetic screening method; Goals; HepG2; Human; In Vitro; Industry; Infection; Investigational Drugs; Lead; Life; Ligands; Measures; Metabolic; Metabolism; Methods; Modeling; Mus; Neuraxis; Oral; Pain; Parasitemia; Parasites; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacopoeias; Plasma; Play; Positioning Attribute; Property; Proteomics; Role; Sepsis; Series; Solubility; Surface Plasmon Resonance; Testing; Therapeutic; Thinness; Toxic effect; Trypanosoma; Trypanosoma brucei brucei; Validation; World Health Organization; absorption; analog; aqueous; chemotherapy; design; drug discovery; efficacy study; human model; improved; indexing; inhibitor/antagonist; kinase inhibitor; knock-down; lapatinib; lead optimization; lipophilicity; mouse model; neglected tropical diseases; novel therapeutics; pre-clinical; protein expression; public health relevance; scaffold; screening

 DESCRIPTION (provided by applicant): Human African trypanosomiasis (HAT) is a neglected tropical disease (NTD) for which new orally available drugs are needed. As an NTD, funds for discovery of new drugs are limited. Therefore, we have been applying a pragmatic approach of "repurposing" human kinase inhibitor scaffolds for anti-trypanosome lead discovery. Starting with the FDA-approved drug lapatinib, which killed cultured bloodstream trypanosomes (EC50 = 1600 nM) and had a selectivity index (SI) = 4 (compared to activity against human HepG2 cells), we designed and synthesized over 380 new analogs in a systematic medicinal chemistry campaign. With an eye towards improving SI, toxicity profile, metabolism, physicochemical properties, and CNS availability, our new series includes advanced hits, which are vastly superior to lapatinib in potency (EC50), SI, and aqueous solubility (Aq. Sol.). They include NEU-1060 (EC50 = 6 nM, SI > 2333), NEU-1912 (EC50 = 24 nM, SI > 1458), and NEU-1953 (EC50 = 420 nM, SI > 100, Aq. Sol. = 43 µM). By directly comparing NEU-1912 to lapatinib, the following key advances are notable (i) 67-fold EC50 improvement; (ii) over 355-fold SI enhancement; and (iii) a 400% increase in lipophilic ligand efficiency (LLE). NEU-1912, in a proof-of-concept study, prolonged life of trypanosome-infected mice as compared to control (untreated) mice. In initial attempts to fine-tune physicochemical properties of NEU-1912, we have increased solubility 48-fold in NEU-2091, and conferred CNS penetration features with NEU-1060. We propose now to focus our efforts on converting the NEU-1912 chemotype into potential leads, by incorporating substituents that improved physicochemical, metabolic or CNS availability of related analogs. For new leads identified, we will perform mode of action, identify the targets for the leads, and genetically validate their importance for trypanosome proliferation. The overarching goal of our project is to deliver five compounds that meet Lead Criteria for HAT in the next five years. Such compounds will be well-positioned for advancement as preclinical investigational new drugs.

 描述（由申请人提供）：非洲人类锥虫病（HAT）是一种被忽视的热带病（NTD），需要新的口服药物来治疗。作为 NTD，用于发现新药的资金是有限的。因此，我们一直在应用“重新利用”人类激酶抑制剂支架的务实方法来发现抗锥虫先导化合物。从 FDA 批准的药物拉帕替尼开始，该药物可杀死培养的血流锥虫 (EC50 = 1600 nM)，选择性指数 (SI) = 4（与针对人类 HepG2 细胞的活性相比），我们在系统的药物化学活动中设计并合成了 380 多种新类似物。着眼于改善 SI、毒性特征、代谢、理化性质和 CNS 可用性，我们的新系列包括先进的热门产品，其在效力 (EC50)、SI 和水溶性 (Aq. Sol.) 方面远远优于拉帕替尼。它们包括 NEU-1060（EC50 = 6 nM，SI > 2333）、NEU-1912（EC50 = 24 nM，SI > 1458）和 NEU-1953（EC50 = 420 nM，SI > 100，Aq. Sol. = 43 µM）。通过直接比较 NEU-1912 与拉帕替尼，以下关键进展值得注意：(i) EC50 提高 67 倍； (ii) SI 增强超过 355 倍； (iii) 亲脂性配体效率 (LLE) 提高 400%。 NEU-1912，在概念验证研究中， 与对照（未治疗）小鼠相比，锥虫感染小鼠的寿命延长。在微调 NEU-1912 理化性质的初步尝试中，我们将 NEU-2091 中的溶解度提高了 48 倍，并赋予 NEU-1060 中枢神经系统渗透特性。我们现在建议集中精力，通过纳入改善相关类似物的物理化学、代谢或中枢神经系统可用性的取代基，将 NEU-1912 化学型转化为潜在的先导化合物。对于确定的新线索，我们将执行作用模式，确定线索的目标，并从基因上验证它们对锥虫增殖的重要性。我们项目的总体目标是在未来五年内提供五种符合 HAT 主要标准的化合物。此类化合物将有利于作为临床前研究新药的发展。