Abstracts Biological Sciences

Structure-based studies in the development of anti-cancer enzyme inhibitors

by Krithika Sundaram

Cancer is one of the most prevalent causes of death worldwide. This thesis focuses on structural studies of two targets from the Aldo-Keto Reductase family (Section A) and Phosphoinositide 3-kinase family (Section B). The Aldo-Keto reductases are associated in the pathogenesis of various diseases including cancer. Section A of the thesis includes structural and functional studies of two aldo-keto reductases: AKR1B14 and AKR1C3. AKR1B14 is a recently identified member of AKR1B subfamily and previous crystallographic studies have revealed the importance of a non-conserved residue in coenzyme binding. The mutagenesis studies of this residue have confirmed the decrease in binding affinity of the coenzyme. The findings presented in this section examine the different AKR1B14 mutants to structurally understand and explain the loss of affinity of coenzyme associated with mutation of this residue using crystallography and molecular modelling. AKR1C3 is believed to be involved in the catalytic metabolism of various steroids. AKR1C3 has gained immense attention as a potential therapeutic target due to its upregulation in breast and prostate cancer. Molecular modelling was used to investigate the structure-activity relationships governing AKR1C3 with various inhibitors and have enabled us in the identification of the structural determinants of inhibition. This information may aid in future development of selective inhibitors for both the targets. The second section of this thesis focuses on Phosphoinositide 3-kinases which are critical regulators of intracellular signalling pathways and are involved in various cellular processes. The class II PI3Ks have gained attention recently as they are believed to be upregulated in certain types of cancers and hence present as a potential therapeutic target. Section B of this thesis investigates the structural features of class II PI3KC2β to identify key residues that could be targeted for inhibitor selectivity. Computational and inhibition studies of various inhibitors of PI3KC2β has presented information that may be useful in future development of class II selective inhibitors. Advisors/Committee Members: Principal Supervisor: Philip Thompson, Supervisor: Ian Jennings, Supervisor: David Chalmers.