Development of Conformation Specific Kinase Inhibitors

构象特异性激酶抑制剂的开发

• 批准号: 6583042
• 负责人: JOHN C PRESCOTT
• 金额: $ 10万
• 依托单位: SUNESIS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6583042
• 关键词: Baculoviridae; X ray crystallography; active sites; antineoplastics; chemical registry /resource; conformation; crosslink; drug design /synthesis /production; drug screening /evaluation; epidermal growth factor; growth factor receptors; kinase inhibitor; phosphorylation; protein purification; quinazolines; thiols

DESCRIPTION (provided by applicant): The long term objective of this proposal is to develop anti-cancer therapeutics which stabilize the inactive conformation of two protein kinases. Most kinase inhibitors compete with ATP for binding to the structurally conserved active site and thus despite high potency in vitro, show modest potency in vivo and limited specificity. This proposal outlines the development of a functionally novel class of kinase inhibitors expected to exhibit greater efficacy and reduced toxicity relative to those currently being developed. A newly emerging "covalent tethering" technology will be used to identify drug-like fragments that bind to a protein target, followed by their assembly through chemical linkage into potent inhibitors. This efficient "screen-then-link" process offers a greater survey of chemical diversity space than typical lead discovery processes. Two prototypic kinases, constrained in their inactive conformation, will be used in these experiments. Extenders will be synthesized and used to modify these kinases, which will subsequently be used to screen our library of >12,000 custom-made sulfhydryl containing drug-like fragments. Promising hit compounds will serve as the starting point for medicinal chemistry lead development. Once optimized, this approach will be applicable to the development of a large number of protein kinase inhibitors with significant anti-cancer therapeutic value.

描述（由申请人提供）：该提案的长期目标是开发稳定两种蛋白激酶的非活性构象的抗癌疗法。 大多数激酶抑制剂与 ATP 竞争与结构保守的活性位点的结合，因此尽管在体外具有高效力，但在体内表现出适度的效力和有限的特异性。该提案概述了功能新颖的激酶抑制剂类别的开发，预计相对于目前正在开发的抑制剂，其具有更高的功效和更低的毒性。一种新出现的“共价束缚”技术将用于识别与蛋白质靶标结合的药物样片段，然后通过化学连接将其组装成有效的抑制剂。这种高效的“筛选然后链接”过程比典型的先导化合物发现过程提供了更广泛的化学多样性空间调查。这些实验将使用两种原型激酶，其非活性构象受到限制。将合成延伸剂并用于修饰这些激酶，随后将用于筛选我们的超过 12,000 个定制的含有巯基的药物样片段库。有前景的热门化合物将成为药物化学先导化合物开发的起点。一旦优化，该方法将适用于开发大量具有显着抗癌治疗价值的蛋白激酶抑制剂。