Lara Molloy: Understanding the Structure Activity Relationship of Mutant-Selective, Allosteric, PI3Kalpha Inhibitors.

<p dir="ltr">Oncogenic mutation to PI3Kalpha occurs in >30% of breast cancer patients, with the most common mutation (H1047R) accounting for 35% of these. Alpelisib is a potent and selective PI3Kalpha inhibitor but causes on-target toxicity such as hyperglycaemia through inhibiting the wildtype kinase. Discovery of a compound (PIK-108) bound in an allosteric pocket involving the R1047 residue created a starting point for drug development. Through synthesis of compounds, and testing in cell-based assays, this project seeks to understand the importance of chemical features for compounds binding in this allosteric pocket and aims to improve the selectivity of compounds for the mutant kinase over wildtype.</p>