Chemistry Core

化学核心

基本信息

批准号：
10230526
负责人：
Zoran Rankovic
金额：
$ 2.56万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
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：
2019-09-19 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10230526
关键词：
ABCG2 gene Acute leukemia Analytical Chemistry Binding Biochemical Biological Biological Assay Biological Availability Biology Biophysics Brain Cell Membrane Permeability Cell model Cells Chemical Agents Chemicals Chemistry Clinical Custom Data Data Analyses Database Management Systems Development Disease Drug Kinetics Evaluation Experimental Models Formulation Fusion Oncogene Proteins Generations Glues Hematologic Neoplasms In Vitro Lead Libraries Maps Mass Spectrum Analysis Methods Molecular Molecular Conformation Molecular Structure NUP98 gene Oncogenes Online Systems Pathway interactions Pediatric Hematology Pharmaceutical Chemistry Pharmaceutical Preparations Plasma Pre-Clinical Model Property Protac Quality Control Role Saint Jude Children&apos s Research Hospital Sampling Secure Solubility Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Structure Technology Testing Therapeutic Tissue imaging Validation Visualization Zoran analytical method aqueous base chemical synthesis data management design drug development drug discovery efficacy evaluation evaluation/testing imaging probe in vivo inhibitor/antagonist instrumentation laboratory equipment lead optimization leukemia milligram novel therapeutic intervention outcome forecast pre-clinical screening small molecule small molecule inhibitor small molecule libraries structural biology tool

项目摘要

Chemistry Core/Summary NUP98-fusion oncogenes (FO) are associated with several pediatric hematological malignancies characterized by poor prognosis. There is a great need for new therapeutic strategies to treat NUP98 FO-driven leukemias. To support Project 1, the Chemistry Core will design focused compound libraries including FDA drugs, preclinical compounds and chemical probes and provide chemistry support to identify compounds that effectively inhibit the NUP98-fusions, or block critical interactions in cell models as proposed in Project 1. To support Project 4, we will optimize the screening hits for potency, selectivity, and drug-like properties to deliver KDM5A-PHD3 inhibitors that meet the criteria for in vitro and in vivo chemical probes. In addition, we will utilize small molecule inhibitors/binders of KDM5A-PHD3 to develop PROTACs (PROteolysis-TArgeting Chimaera) targeting KDM5A PHD3 and selectively degrading NUP98-KDM5A. We propose to evaluate, further optimize, select and formulate compounds for pre-clinical in vivo efficacy evaluation proposed in Project 4. The Chemistry Core consists of three highly integrated teams that collectively provide state-of-the-art chemical probe design, synthesis, and evaluation capabilities: the Analytical Chemistry Center (ATC) provides an extensive battery of analytical methods to evaluate compound chemical, biophysical and ADME properties, and routinely elucidates structures of metabolites and other unknown molecules, develops highly customized bioanalytical methods, and formulations for in vivo studies. The Medicinal Chemistry Center (MCC) focuses on identification and development of potent and selective chemical probes for proof-of-concept studies in cells and in vivo preclinical models. The Chemical Biology Center (CBC) applies advanced chemical biology methods to develop sophisticated chemical tools designed to map and interrogate disease-related biological pathways. The CBC chemical tool-box includes PROTACs, molecular glues, pool-down, photoactivatable and imaging probes. For example to support PROTAC platform CBC developed an FP-CRBN assay and built a library of >50 linker-E3 intermediates suitable for rapid “click” chemistry-based synthesis of the final PROTAC target molecules.

化学核心/总结 NUP98 融合癌基因 (FO) 与多种儿童血液恶性肿瘤相关非常需要新的治疗策略来治疗 NUP98 FO 驱动的白血病。为了支持项目 1，化学核心将设计重点化合物库，包括 FDA 药物、临床前化合物和化学探针，并提供化学支持来识别该化合物有效抑制 NUP98 融合，或阻断细胞模型中的关键相互作用，如项目 1 中提出的。支持项目 4，我们将优化筛选命中的效力、选择性和类药特性，以提供此外，我们将利用符合体外和体内化学探针标准的 KDM5A-PHD3 抑制剂。 KDM5A-PHD3 的小分子抑制剂/结合剂，用于开发 PROTAC（PROteolysis-Targeting Chimaera）我们建议针对 KDM5A PHD3 并选择性降解 NUP98-KDM5A。选择并配制用于项目4中提出的临床前体内功效评估的化合物。化学核心由三个高度整合的团队组成，共同提供最先进的化学探针设计、合成和评估能力：分析化学中心 (ATC) 提供广泛的分析方法来评估化合物的化学、生物物理和 ADME 特性，并定期阐明代谢物和其他未知分子的结构，开发高度定制的药物化学中心 (MCC) 专注于体内研究的生物分析方法和配方。鉴定和开发用于细胞概念验证研究的有效和选择性化学探针体内临床前模型。化学生物学中心 (CBC) 应用先进的化学生物学方法。开发复杂的化学工具，旨在绘制和询问与疾病相关的生物途径。 CBC 化学工具箱包括 PROTAC、分子胶、pool-down、光活化和成像例如，为了支持 PROTAC 平台，CBC 开发了 FP-CRBN 检测并建立了一个库。 >50 个连接子-E3 中间体，适用于最终 PROTAC 靶标的基于快速“点击”化学的合成分子。