SVC112: From Hummingbirds to Head and Neck Cancer.

Many organs in a Drosophila melanogaster larva have a remarkable ability to regenerate. Studies of these have facilitated genetic and cell biological analyses that uncovered the role of evolutionarily conserved signaling molecules and transcriptional circuits with components that are dispensable for organogenesis but essential for regeneration. To supplement genetic screens, we designed a screen for chemical inhibitors of recovery and regeneration after damage by ionizing radiation, specifically X-rays. The primary screen used mutants in the Drosophila homologs of p53 and Checkpoint Kinase 1 to mimic the loss of p53 and deregulation of cell cycle checkpoints found in human cancers. The hits from the primary screen were counter-screened against wild-type larvae to select molecules that show differential effects on mutant over wild-type tissues. This screen found chemically distinct inhibitors of translation elongation, suggesting that this step in macromolecular synthesis is particularly important for tissues to survive radiation damage. One of these molecules, bouvardin (NSC259968), was further developed through structure-activity relationship analysis to produce a proprietary derivative called SVC112. Bouvardin and SVC112 are found to act on the human ribosome by a previously unknown mechanism. Discovery of bouvardin and development of SVC112 as an oncology agent toward human trials will be discussed in this chapter.