Phenoxazines Inhibit Akt and Induce Apoptosis

Western Illinois University, Macomb IL

Investigators

Abstract

[unreadable] 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. [unreadable] 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. [unreadable] [unreadable] [unreadable]