Although patient outcome following acute myocardial infarction (AMI) has improved, methods to limit ischaemia and reperfusion (IR) injury in AMI patients remain an important unmet clinical need. Treatment has improved, but long-term outcome is still poor with many patients going on to develop heart failure. Experiments over the past ~20 years have identified the PI3-kinase / AKT signalling pathway (referred to as the "Reperfusion Injury Salvage Kinase" pathway) as centrally involved in many cardioprotective drugs able to reduce myocardial infarct size after IR. The PI3Kalpha isoform is essential for many cardioprotective strategies in mice. We recently developed a novel small molecule called UCL-TRO-1938 or 1938, which is able to enter cells and directly bind to and allosterically activate PI3Kalpha, without affecting other isoforms. By thereby activating the RISK pathway, 1938 can protect the hearts of mice and rats from injury. It also stimulates cell proliferation and neurite outgrowth in vitro. After local in vivo administration, it enhances nerve regeneration following nerve crush injury. This novel chemical tool allows direct probing of the PI3Kα signalling pathway and a new approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes through short-term activation for tissue protection and regeneration.