Metal Complexes as Protein Kinase Inhibitors

作为蛋白激酶抑制剂的金属配合物

• 批准号: 7048663
• 负责人: ERIC MEGGERS
• 金额: $ 21.81万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048663
• 关键词: X ray crystallography; adenine; adenosine triphosphate; binding sites; chelating agents; chemical stability; chemical synthesis; combinatorial chemistry; kinase inhibitor; ligands; metal complex; platinum; ruthenium

DESCRIPTION (provided by applicant): The design and synthesis of novel structural platforms which can project substituents into multiple regions of the receptor space is an important goal in the search for new leads for the discovery of molecular probes and eventually drugs. The proposed research intends to investigate the versatility of organometallic and inorganic compounds as structural scaffolds for the design of specific enzyme inhibitors. Such metal-ligand assemblies will allow convergent and economical synthetic approaches and will give access to structural motifs that differ from purely organic molecules. The specific goal of this research program encompasses the development of inert metal complexes that target the ATP-binding site of protein kinases. ATP-competitive inhibitors generally reach into the adenine binding pocket and form hydrogen bonds with the peptide backbone. Metal complexes with one ligand that bears the main structural features of one of these scaffolds can copy their mode of action. Additional ligands in the coordination sphere of the metal are intended to undergo specific contacts with other parts of the active site. Main focus will be the transformation of the class of indolocarbazole and indirubin inhibitors into metal complex scaffolds. This project includes the design and synthesis of adenine pocket-binding chelate ligands, the synthesis and examination of metal complexes, rational inhibitor design by molecular modeling, x-ray crystallographic studies of protein kinase domains in complex with metal compounds, structure-activity relationships, and combinatorial chemistry with metal complexes. The project bridges the fields of organic and inorganic medicinal chemistry by using metal centers as chemically inert structural scaffolds for drug design. This novel approach might lead to a new class of therapeutics.

描述（由申请人提供）：新型结构平台的设计和综合，可以将取代基投射到受体空间的多个区域，这是寻找新铅的重要目标，以发现分子探针和最终药物。拟议的研究旨在研究有机金属和无机化合物作为特定酶抑制剂设计的结构支架的多功能性。这种金属配体组件将允许收敛和经济的合成方法，并可以访问与纯有机分子不同的结构基序。 该研究计划的具体目标包括针对蛋白激酶ATP结合位点的惰性金属复合物的发展。 ATP竞争激烈的抑制剂通常伸入腺嘌呤结合口袋，并与肽主链形成氢键。带有其中一个脚手架之一的主要结构特征的配体的金属配合物可以复制其作用方式。金属的配位球体中的其他配体旨在与活性位点的其他部分进行特定的接触。主要的重点将是将吲哚可核糖和印度氨基蛋白抑制剂类别转化为金属复合支架。该项目包括设计和合成腺嘌呤口袋结合螯合配体，金属络合物的合成和检查，通过分子建模的合理抑制剂设计，X射线晶体学对金属化合物中蛋白激酶结构域的X射线晶体学研究，结构 - 活性关系，结构 - 活性关系以及与金属配合物的结合化学。 该项目通过将金属中心用作药物设计的化学惰性结构支架来桥接有机和无机药物的领域。这种新颖的方法可能会导致新的治疗疗法。