Scientific Core - Compound Optimization and Prioritization.

科学核心 - 复合优化和优先级排序。

基本信息

批准号：
10388410
负责人：
Anna Upton
金额：
$ 85.09万
依托单位：
GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10388410
关键词：
Antitubercular Agents Biochemical Biological Assay Biological Availability Cells Collaborations Development Drug Industry Drug Kinetics Drug Targeting Drug resistant Mycobacteria Tuberculosis Evaluation Excretory function Goals Human Resources In Vitro Investigational Drugs Lead Metabolism Modeling Mus Mycobacterium tuberculosis Names Oral Peptides Pharmaceutical Chemistry Process Production Proteins Provider Regimen Research Contracts Rodent Safety Series Sterilization Structure Toxic effect absorption base computational chemistry cost design drug candidate drug development drug discovery drug-sensitive experience flexibility in vivo in vivo evaluation innovation lead optimization peptidomimetics pharmacokinetics and pharmacodynamics pre-clinical programs research and development safety study scale up screening small molecule structural biology success translational study virtual

项目摘要

The Specific Aim of Core A is to provide an integrated structure-guided lead identification and optimization effort, in collaboration with Projects 1–4 and Core B, with the ultimate objective of delivering advanced leads for entry into translational studies comprising early development (Core C) toward an Investigational New Drug IND filing, and preclinical regimen development and pharmacokinetic/pharmacodynamic (PKPD) studies (Project 4). This will be accomplished through two Activities: (1) Lead Identification, to identify a lead compound within a series, with demonstrated efficacy in Mycobacterium tuberculosis (Mtb)-infected mice, that is sufficiently well characterized to allow development of a clear lead optimization plan, and (2) Lead Optimization and Compound Prioritization, to optimize the lead(s) identified in Activity 1 to meet the criteria required to initiate non-GLP safety studies (in Core C), and proceed to regimen development in Project 4. To conduct these activities, Core A will provide capabilities including medicinal chemistry (design and synthesis); structural biology; computational chemistry; in vitro and in vivo absorption, distribution, metabolism and excretion (ADME) and pharmacokinetic (PK) studies; in vitro safety assays; preliminary toxicity studies, and scale-up synthesis. These capabilities will support selection of compounds from Projects 1–3, for further progression. together with evaluations of antituberculosis activity through Core B. The Core will innovate by providing state-of-the-art structural and computational approaches in designing small molecules and peptides and leverage the latest developments in understanding of oral bioavailability of large peptides and peptidomimetics. Effective direction and successful implementation of these capabilities and processes is critical to the overall goals of the CETR, which include selection of drug candidates against three drug targets, from Projects 1–3. Core A will be led by TB Alliance, which is ideally suited to the task, with extensive experience in drug discovery and development and a track record of success: the Core A PI, Dr. Upton, and the key personnel, have collectively over 100 years of experience within the pharmaceutical industry and TB Alliance in drug discovery and development. Over the last two years, the team has advanced four projects into IND-enabling studies and filed three INDs, with two more expected in 2018. The team also manages a mature portfolio of lead Identification and lead optimization projects. The Core will operate using the successful virtual R&D model of TB Alliance: All activities will be carried out with partners and contract research organizations (CROs). For each series, a unique, tailored program of studies will be developed where partners and CROs will be selected based on need, cost, quality, and timing, leveraging the expertise and specializations of the named organizations that will participate (such as Proteros and Schrodinger). This extremely flexible, nimble, and efficient setup will allow the Center to prosecute multiple projects with diverse needs, without being reliant on any one approach or provider. This setup is possible due to the experience and expertise of the Core staff in building and directing such programs for TB Alliance.

核心 A 的具体目标是提供集成的结构引导先导化合物识别和优化与项目 1-4 和核心 B 合作，最终目标是为进入转化研究，包括针对研究性新药 IND 的早期开发（核心 C）归档、临床前方案开发和药代动力学/药效学 (PKPD) 研究（项目 4）。这将通过两项活动来完成：(1) 先导化合物识别，以识别药物中的先导化合物。系列，在结核分枝杆菌 (Mtb) 感染的小鼠中已证明有效，效果足够好其特点是允许制定明确的先导化合物优化计划，以及 (2) 先导化合物优化和化合物确定优先级，优化活动 1 中确定的先导化合物，以满足启动非 GLP 安全性所需的标准研究（核心 C），并继续项目 4 中的治疗方案开发。为了开展这些活动，核心 A 将提供药物化学（设计和合成）等能力；化学；体外和体内吸收、分布、代谢和排泄（ADME）和药代动力学（PK）研究；体外安全性测定；初步毒性研究以及放大合成。支持从项目 1-3 中选择化合物，以进行进一步的进展以及评估。通过核心 B 进行抗结核活性。核心将通过提供最先进的结构和设计小分子和肽并利用最新发展的计算方法了解大肽和肽模拟物的口服生物利用度的有效方向和成功。这些能力和流程的实施对于 CETR 的总体目标至关重要，其中包括结核病联盟将领导项目 1-3 中针对三个药物靶标的候选药物的选择。非常适合这项任务，在药物发现和开发方面拥有丰富的经验以及跟踪成功记录：核心 PI、Upton 博士和关键人员总共拥有 100 多年的经验在过去的两年里，制药行业和结核病联盟在药物发现和开发方面，该团队已将四个项目推进 IND 支持研究，并提交了三个 IND，预计还有两个项目 2018 年。该团队还管理着成熟的先导化合物识别和核心优化项目组合。将使用结核病联盟成功的虚拟研发模式进行运营：所有活动都将与合作伙伴一起进行和合同研究组织 (CRO) 对于每个系列，都将有一个独特的、量身定制的研究计划。将根据需求、成本、质量和时间选择合作伙伴和 CRO，并利用将参与的指定组织（例如 Proteros 和 Schrodinger）的专业知识和专业知识。这种极其灵活、灵活和高效的设置将使该中心能够参与具有不同性质的多个项目。由于经验和经验，这种设置是可能的，而不依赖于任何一种方法或提供商。核心人员在为结核病联盟制定和指导此类项目方面的专业知识。