Understanding and manipulating stress signalling: from mechanisms to therapeutics

Numerous stress-signalling pathways are required to ensure cell survival in the face of challenges. My lab aims at identifying strategies that harness these signalling pathways to enhance cellular resilience, a modality generically applicable to improve fitness in diverse diseases, including the age-related degenerative diseases. We recently discovered that potent and optimized ATP-competitive inhibitors of the kinases of the integrated stress response (ISR), PERK and PKR, can paradoxically activate this pathway by directly binding to and activating a sister ISR kinase, GCN2. This proposal aims at developing this exciting finding, of broad relevance. We will dissect the molecular mechanisms of chemical activation of GCN2, identify selective chemical activators of GCN2 and assess their therapeutic potential in diverse disease models, starting with those with a genetic link with the ISR. We will extend the study of ISR kinases activation to reveal the mechanisms by which they recruit their substrate. This research programme will bring fundamental discoveries applicable to a large family of enzymes, with a translational potential relevant to a group of devastating and so far incurable diseases.