Lead optimization of hits identified from virtual and experimental screens of multiple industrial libraries DNDi

从多个工业库 DNDi 的虚拟和实验屏幕中识别的先导化合物优化

• 批准号: 10358642
• 负责人: Lori Ferrins
• 金额: $ 40.32万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-22 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358642
• 关键词: Affect; Animal Model; Attention; Biological Assay; Cellular Assay; Chagas Disease; Chronic; Clinic; Collection; Data; Development; Development Plans; Disease; Disease model; Dose; Drug Industry; Drug Kinetics; Drug Screening; Drug resistance; Eye; Funding; Goals; In Vitro; Industrialization; Industry; Institution; Investments; Lead; Leishmania; Leishmania donovani; Libraries; Measures; Metabolic; Morbidity - disease rate; National Institute of Allergy and Infectious Disease; Parasitemia; Parasites; Parasitology; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Preparation; Process; Property; Regimen; Series; Services; Solubility; Testing; Therapeutic; TimeLine; Toxic effect; Toxicology; Translations; Treatment Failure; Trypanosoma cruzi; Visceral Leishmaniasis; Work; World Health Organization; acute infection; aqueous; chemical stability; clinical candidate; cost; design; drug discovery; drug metabolism; drug-sensitive; efficacy study; experience; financial incentive; in vivo; in vivo Model; lead optimization; meetings; member; mortality; neglect; neglected tropical diseases; pathogen; pre-clinical; programs; safety assessment; scale up; screening; therapeutic development; virtual; virtual screening

SUMMARY/ABSTRACT Neglected tropical diseases (NTDs) are a leading cause of morbidity and mortality, affecting over 1 billion people worldwide. Given the lack of financial incentive for the for-profit pharmaceutical industry, there is little translation seen from in vitro drug screening assays into in vivo efficacy studies. We propose to progress hit compounds, identified from pharmaceutical company compound libraries, through to pre-clinical candidate status. To achieve this, we have engaged with the Drugs for Neglected Diseases Initiative (DNDi), effectively aligning ourselves with several partners who bring deep expertise from industry, in medicinal chemistry, drug metabolism and pharmacokinetics, and from institutions that contribute parasitology experience and a proven ability to progress drugs for NTDs into the clinic and beyond. Such a project team is singular across the NTD drug discovery landscape and is a strength of this proposal. We will accomplish the proposed project goals by focusing our attention on the design of compounds which meet the Target Product Profile (TPP) for visceral leishmaniasis and Chagas disease. DNDi's Booster program identifies starting hits through a unique process, involving iterative screening and testing cycles of 7 pharmaceutical company compound libraries. The compound members of each library are well annotated with known pharmacological activity, and computationally predicted and/or experimentally measured properties (including aqueous solubility, metabolic stability, in vitro toxicology etc.), enabling the rapid identification of potential liabilities. This proposal focuses on four chemotypes that emerged from the Booster program that consist of a large number of validated hits against Leishmania spp. and Trypanosoma cruzi. The R21 phase will be focused on hit-to-lead optimization and the down-selection of the four chemotypes to two. We will identify compounds that demonstrate proof-of-concept disease-modifying effects in animal models of the respective diseases. Further, we will profile those compounds that demonstrate positive effects on parasitemia in vivo to identify potential liabilities, which will become the focus of the candidate-seeking medicinal chemistry campaign outlined in the R33 phase. The R33 phase is focused on the lead-to-preclinical candidate optimization of the prioritized chemotypes. We are uniquely placed to achieve this goal as we are collaborating directly with DNDi and Celgene Corporation throughout this project. At the completion of the R33 phase we will deliver a complete data package on two compounds for each disease (one candidate, one backup) that meets the respective TPP, and which will be used to justify IND-enabling studies.

总结/摘要 被忽视的热带病是发病和死亡的主要原因，影响超过10亿人。 世界各地的人们。鉴于营利性制药行业缺乏财政激励， 从体外药物筛选试验到体内功效研究的转化。我们建议进行打击 从制药公司化合物库中鉴定的化合物，直至临床前候选化合物 status.为了实现这一目标，我们与被忽视疾病药物倡议（DNDi）进行了有效合作， 我们与几个合作伙伴保持一致，他们带来了来自行业的深厚专业知识，在药物化学，药物 代谢和药代动力学，并从机构贡献寄生虫学经验和证明 将NTD药物进展到临床及其他领域的能力。这样的项目团队在整个新台币都是独一无二的 药物发现的前景，是这个建议的力量。 我们将通过将注意力集中在化合物的设计上来完成所提出的项目目标 其符合内脏利什曼病和恰加斯病的目标产品概况（TPP）。DNDi的助推器 该计划通过一个独特的过程识别起始命中，包括迭代筛选和测试周期为7 制药公司化合物库。每个文库的化合物成员都用 已知的药理学活性和计算预测和/或实验测量的性质 （包括水溶性、代谢稳定性、体外毒理学等），能够快速识别 潜在的责任。这项提案的重点是从助推器计划中出现的四种化学型， 包括大量针对利什曼原虫属的经验证的命中。和克氏锥虫。 R21阶段将专注于命中-先导优化和四种化学型的向下选择 到两个我们将确定在动物模型中证明概念验证疾病修饰作用的化合物 各自的疾病。此外，我们还将分析那些表现出积极作用的化合物， 寄生虫血症在体内，以确定潜在的负债，这将成为候选人寻求药用的重点 R33阶段概述的化学活动。 R33阶段的重点是优先化学型的临床前候选优化。 我们处于独特的地位，以实现这一目标，因为我们正在与DNDi和Celgene公司直接合作 在这个项目中。在R33阶段完成后，我们将在两个 符合各自TPP的每种疾病的化合物（一种候选，一种备用）， 用于证明IND使能研究的合理性。