Chemistry Seminar Presented by Dr. Gregory Craven

The Department of Chemistry is pleased to host Dr. Gregory Craven for a seminar on Monday, December 2. Title: "Mutant-selective AKT1 inhibition via lysine targeting and neo-zinc chelation" Abstract: Mutations in the kinase AKT1, especially the E17K mutation, drive oncogenic signaling in many solid tumors. In clinical studies, pan-AKT inhibitors cause dose-limiting hyperglycemia, motivating the search for mutant-selective inhibitors. To address this, I exploited the E17K mutation to design allosteric, lysine-targeted salicylaldehyde inhibitors with selectivity for AKT1(E17K) over wild type AKT paralogs, a major challenge given the presence of three conserved lysines near the allosteric site. Structural studies revealed an unexpected mode of covalent inhibition involving neo-zinc coordination, which drives exceptional selectivity and residence-time in cellular models and tumor xenografts. This approach opens a pathway for the selective targeting of other oncogenic lysine mutations in cancer and motivates the search for new pharmacological opportunities by exploiting ligand-induced metal chelation. Host: Chemistry Department Chemical Biology Series