Small molecule modulation of the cell cycle: Discovery of anticancer compounds that induce G1- and M-phase cell cycle arrest and characterization of their modes of action.

摘要

The elucidation of molecular targets of bioactive small organic molecules remains a significant challenge in modern biomedical research and drug discovery. This dissertation details two phenotype-based discovery projects. Chapter 1 highlights the importance of the identification of new bioactive small molecules in drug discovery, and provides an overview of strategies used to elucidate the protein target of lead molecules discovered through phenotype-based screening campaigns. Chapter 2 details efforts made to elucidate the mode of action and protein target of a class of triphenylmethylamide (TPMA) pharmacophores. This scaffold was pursued for its ability to induce G1 cell cycle arrest and apoptosis in melanoma cells, a cell type notoriously resistant to several common classes of chemotherapeutics. It was determined that TPMAs act via disrution of normal endoplasmic reticulum function, inducing apoptosis through initiation of the unfolded protein response. Chapter 3 describes discovery of tubulin as the molecular target of 8H and other phenylcinnamides that induce M-phase cell cycle arrest and cell death in a variety of cell lines. Also presented in an appendix are the summarized results of an attempt to design isozyme-specific inhibitors of the enzyme Vault Parp using a fragment based in silico screening approach.