Genetic mutations in genes called oncogenes are major drivers in the development and progression of cancer. More than 30% of tumours contain mutations in genes that result in the activation of the PI 3-kinase signalling pathway in cells, driving the development of many forms of cancer. Drugs that block this pathway are thus an important goal for many research groups, including our own. We have previously developed one drug (PWT33597), funded by an HRC grant, which is now in Phase I clinical trial. The current programme will use this experience to answer major unresolved drug design questions, including; how selective for PI 3-kinase should they be?; how much and for how long do we need to shut the enzyme down?; how do we overcome drug resistance mechanisms? We believe that these questions are important to answer to guide the development of more effective "second generation" inhibitors of PI 3-kinase.