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是肿瘤发生中核心参与者的关键作用。 AKT在各种人类肿瘤中过表达，其表达增加也与疾病进展有关。由于已经在人类癌症中观察到了AKT激活，因此正在努力开发特定的Akt抑制剂作为癌症治疗剂。目前，在诊所中没有针对AKT的特定抑制剂。因此，小分子的设计和开发专门抑制了AKT的激酶活性及其在癌细胞中其信号转导途径是一种有吸引力的方法来开发新的癌症治疗剂。在此应用中，提出了一系列与Akt特定抑制剂发展有关的一系列研究：1。新苯氧嗪的合成，具有增加的效力，并筛选它们以抑制AKT及其下游靶标的激活而不会影响上游目标或MAP激酶途径的能力。 2。确定苯氧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。执行激酶测定和酶动力学实验，以揭示苯氧嗪专门抑制Akt激活的机制。 4。评估最有效的抑制剂，其诱导癌细胞凋亡的能力。 预计这些新化合物将提供有效的癌症治疗，并具有最小的毒性副作用。这些研究的长期目标是开发用于常规细胞毒性剂的替代方法，作为癌症患者的潜在治疗疗法。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。但是，这些超出了当前应用程序的范围，但将构成未来任何建议的基础。