There is still a need for cardioprotective strategies beyond rapid reperfusion - and there is a need for innovative new strategies. All previous strategies that were promising under experimental conditions have failed in clinical translation. It makes sense to focus the development of a new drug on a key protein in a signaling cascade known to be involved in cardioprotection, and this is what the authors did here. They performed a series of screening experiments to identify an isoform-specific PI3Kα activator. UCL-TRO-1938 allosterically activates PI3Kα through the PI3Kα catalytic cycle and induces conformational changes in the PI3Kα structure. After verifying the efficacy in vitro, they have gone into cell model on human A549 cells and used as a marker of PI3Kα activation the AKT phosphorylation. UCL-TRO-1938 not only works in cell culture, it also reduced infarct size in vitro in isolated perfused rat hearts, but also in vivo by i.v. application 15 min before reperfusion in mice.
Thus, this study identifies a novel chemical tool to directly activate the cardioprotective PI3Kα pathway. Now, the potential of kinase activation for therapeutic purposes needs to be re-evaluated in the next steps, i.e. by translating the rodent results to large animals before clinical trials are performed. This is the only way to increase the likelihood that novel cardioprotective interventions will be translated into clinical practice for the benefit of patients.
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