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/摘要 NUP98融合癌基因（FO）与几种儿童血液恶性肿瘤有关预后不良。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的化合物库，包括FDA药物，临床前化合物和化学问题，并提供化学支持，以识别化合物有效地抑制NUP98 - 融合，或阻止项目1中提出的细胞模型中的临界相互作用。支持项目4，我们将优化筛选效果，选择性和类似药物的特性符合体外和体内化学问题标准的KDM5A-PHD3抑制剂。此外，我们将使用 KDM5A-PHD3的小分子抑制剂/粘合剂，以开发protac（靶向蛋白水解靶向嵌合体）针对KDM5A PHD3并有选择地降解NUP98-KDM5A。我们建议评估，进一步优化，选择并制定化合物，用于项目4中提出的体内效率评估。化学核心由三个高度集成的团队组成，这些团队共同提供最先进的化学品探针设计，合成和评估功能：分析化学中心（ATC）提供了一个广泛的分析方法，用于评估复合化学，生物物理和ADME特性，并经常阐明代谢物和其他未知分子的结构，会发展高度定制生物分析方法和用于体内研究的公式。药物化学中心（MCC）的重点在细胞和体内临床前模型。化学生物学中心（CBC）将高级化学生物学方法应用于开发精致的化学工具，旨在绘制和询问与疾病有关的生物学途径。 CBC化学工具盒包括Protac，分子胶，池降低，光活化和成像问题。例如，支持Protac Platform CBC开发了FP-CRBN分析，并建立了一个库 > 50个Linker-E3中间体适用于最终Protac目标的基于“单击”化学的合成分子。