Hit-to-lead optimization for sleeping sickness drug discovery

昏睡病药物发现的先导化合物优化

基本信息

批准号：
9078330
负责人：
KOJO A. MENSA-WILMOT
金额：
$ 64.03万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-19 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9078330
关键词：
Affinity Chromatography African Trypanosomiasis 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 Modeling Mus Neuraxis Oral Parasitemia Parasites Penetration Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacopoeias Plasma Play Positioning Attribute Property Proteomics Role Sepsis Series Solubility Surface Plasmon Resonance Testing Therapeutic Toxic effect Trypanosoma Trypanosoma brucei brucei Validation World Health Organization absorption analog aqueous chemotherapy counterscreen design drug discovery improved indexing inhibitor/antagonist killings kinase inhibitor knock-down lapatinib meetings mouse model neglected tropical diseases novel therapeutics pre-clinical protein expression public health relevance scaffold screening

项目摘要

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（由适用提供）：非洲人类锥虫病（HAT）是一种被忽视的热带疾病（NTD），需要新的口服药物。作为NTD，发现新药的资金有限。因此，我们一直在采用一种务实的方法，即“重新利用”人类激酶抑制剂支架来进行抗肌液病。从FDA批准的药物Lapatinib开始，该药物杀死了培养的血液锥虫（EC50 = 1600 nm），并具有选择性指数（SI）= 4（与针对人HepG2细胞的活性相比，我们设计并合成了380多个在系统的系统医学化学运动中。为了改善SI，毒性特征，代谢，物理性质和CNS的可用性，我们的新系列包括高级命中，它们在效力（EC50），SI和水溶液（aq。Sol。）中优于Lapatinib。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）。通过将NEU-1912与Lapatinib进行直接比较，以下主要进步值得注意（i）67倍的EC50改善；（ii）超过355倍的SI增强；（iii）亲脂配体效率（LLE）增加了400％。 NEU-1912，概念验证研究，与对照（未治疗）小鼠相比，锥虫感染的小鼠的寿命长时间。在最初尝试微调NEU-1912的物理特性时，我们在NEU-2091中提高了48倍的溶解度，并以NEU-1060进行了CNS渗透特征。我们现在建议通过增加相关类似物的物理，代谢或中枢神经系统的可用性来将努力集中在将NEU-1912化学型转化为潜在潜在客户上。对于已确定的新潜在客户，我们将执行行动方式，确定铅的目标，并在基因上验证其对锥虫增殖的重要性。我们项目的总体目标是提供五种在未来五年内符合HAT的铅标准的化合物。这些化合物将被置于临床前研究新药的发展中。