Discovering inhibitors of cell surface receptor function as the basis for novel therapeutics to treat cancer

© 2020 Larissa DoughtyAs our understanding of the molecular changes that trigger and potentiate cancer increases, cancer therapies are becoming increasingly refined and specifically targeted to increase efficacy and reduce side effects. Structure-based rational drug design has become a common method to identify lead compounds that can be further optimised as potential drug candidates. Cell-surface receptors that undergo changes in expression and activity in cancer and can be manipulated to elicit a therapeutic effect by a binding ligand that affects protein function make ideal targets. CD33 is a transmembrane protein from the sialic acid-binding immunoglobulin like lectin (siglec) family. It is expressed on the leukemic blasts from the majority of patients with acute myeloid leukemia (AML) but is not expressed on normal stem cells. CD33 also undergoes endocytosis when bound by CD33 antibodies. This expression pattern and the ability to potentially internalise a cytotoxic compound into the cancer cell implicates CD33 as a target for therapeutic intervention. Another cell surface receptor, CD151, from the tetraspanin family of proteins, has been shown to be over expressed in a variety of cancers. CD151 and its binding partner integrin, are key signalling proteins in cell motility and adhesion, which is a driver for cancer metastasis. Prostate cancer, which is only lethal once metastasised, could be effectively treated if metastasis could be controlled. Targeting the specific interaction between CD151 and integrin by inhibiting the unique CD151-integrin binding site has been shown to inhibit cell motility in cell based assays and is a promising target for small-molecule inhibitors. The specific aims of this thesis are to explore structural and functional aspects of CD33 and CD151, that are validated targets for certain cancers. Insights into the structure of these proteins will be used to identify small molecules that modulate protein function to develop novel strategies to treat common cancers in humans