Phenoxazines Inhibit Akt and Induce Apoptosis

吩恶嗪抑制 Akt 并诱导细胞凋亡

• 批准号: 6951325
• 负责人: Netkal M. Made Gowda
• 金额: $ 18.56万
• 依托单位: WESTERN ILLINOIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6951325
• 关键词: antineoplastics; apoptosis; binding sites; drug design /synthesis /production; drug screening /evaluation; enzyme activity; hydropathy; kinase inhibitor; neoplastic cell; oxazine; pharmacokinetics; protein binding; protein structure function; serine threonine protein kinase; tissue /cell culture

DESCRIPTION (provided by applicant): Mounting evidence has confirmed the crucial role of Akt as a central player in tumorigenesis. Akt is overexpressed in a variety of human tumors and its increased expression also correlates with disease progression. As Akt activation has been observed in human cancers, intense efforts are underway to develop specific Akt inhibitors as cancer therapeutics. At present there are no specific inhibitors directed against Akt in the clinic. Therefore, the design and development of small molecules that specifically inhibit the kinase activity of Akt and its signal transduction pathway in cancer cells is an attractive approach for the development of new cancer therapeutic agents. In this application, a series of studies that relate to development of specific inhibitors of Akt are proposed: 1. Synthesis of new phenoxazines with increased potency and to screen them for their ability to inhibit the activation of Akt and its downstream targets without affecting the upstream targets or MAP kinase pathway. 2. Determine whether phenoxazines inhibit the activation of Akt by binding to PH domain or ATP-site of the protein. 3. Perform kinase assays and enzyme kinetics experiments to unravel the mechanism by which phenoxazines specifically inhibit the activation of Akt. 4. Evaluate the most potent inhibitor for its ability to induce apoptosis in cancer cells. It is expected that these new compounds will provide effective treatment of cancer with minimum toxic side effects. The long-term goal of these studies is to develop alternative approaches to conventional cytotoxic agents as potentially curative therapy for cancer patients. If successful, we anticipate that compounds that are highly specific and potent against Akt could be tested in xenograft model. However, these are beyond the scope of the current application, but will form the basis for any future proposals.

描述（由申请人提供）：越来越多的证据证实了 Akt 作为肿瘤发生中的核心角色的关键作用。 Akt 在多种人类肿瘤中过度表达，其表达增加也与疾病进展相关。由于在人类癌症中观察到 Akt 激活，因此正在大力开发特定的 Akt 抑制剂作为癌症治疗药物。目前临床上尚无针对Akt的特异性抑制剂。因此，设计和开发特异性抑制癌细胞中Akt激酶活性及其信号转导途径的小分子是开发新型癌症治疗剂的一个有吸引力的方法。在本申请中，提出了一系列与开发 Akt 特异性抑制剂相关的研究： 1. 合成具有更高效力的新型吩恶嗪，并筛选它们抑制 Akt 及其下游靶点激活而不影响上游靶点的能力目标或 MAP 激酶途径。 2. 确定吩恶嗪是否通过与蛋白质的 PH 结构域或 ATP 位点结合来抑制 Akt 的激活。 3. 进行激酶测定和酶动力学实验，以揭示吩恶嗪特异性抑制 Akt 激活的机制。 4. 评估最有效的抑制剂诱导癌细胞凋亡的能力。 预计这些新化合物将以最小的毒副作用提供有效的癌症治疗。这些研究的长期目标是开发传统细胞毒性药物的替代方法，作为癌症患者的潜在治疗方法。如果成功，我们预计可以在异种移植模型中测试对 Akt 高度特异性和有效的化合物。然而，这些超出了当前应用的范围，但将构成任何未来提案的基础。