MEDI 281 |
| Amplification, overexpression, and elevated activation of Akt have been detected in many human malignancies making it a critical target for cancer therapy. The substrate-binding site offers a large number of potential interactions to an appropriately designed small molecule providing an evolutionary handle for the development of selective inhibitors. Here, we report the progression of substrate-mimetic inhibitors towards the development of a potent, small molecule inhibitor of Akt. A simple series of peptidomimetic inhibitors was generated directly from the minimal GSK3 substrate sequence to provide peptidomimetic inhibitors that demonstrate low micromolar activity in vitro, induce apoptosis, and prevent growth in OV3 cancer cells. The first attempt at a completely non-peptidic substrate-mimetic was successful in providing potent, more rigid, lipophilic inhibitors that lack stereocenters and are significantly smaller in size than the GSK3 peptide. Modifications of these inhibitors will provide a useful set of molecular probes to assist in the validation of Akt as a potential target for anticancer drug design. |
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Medicinal Chemistry Award Symposium
9:00 AM-12:10 PM, Tuesday, 12 September 2006 Moscone Center -- Room 102, Oral
Division of Medicinal Chemistry |