Discovering Small Molecule Activators of Stress-Responsive Signaling

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PROJECT SUMMARY Endoplasmic reticulum (ER) stress is implicated in the onset and pathogenesis of diverse age-related diseases, including many neurodegenerative disorders. In these diseases, ER stress leads to disruptions in nearly all aspects of cellular physiology. To protect tissues against ER stress, mammals evolved the unfolded protein response (UPR) – a stress-responsive signaling pathway comprising three signaling arms activated downstream of the ER membrane stress-sensing proteins IRE1, ATF6, and PERK. In response to ER stress, these pathways are activated to promote transcriptional remodeling of multiple biological pathways to both mitigate the initiating ER insult and prevent pathologic disruptions in cell physiology. This remodeling is primarily mediated by the UPR-associated transcription factors XBP1s (activated downstream of IRE1) and ATF6 (a cleaved product of full-length ATF6). These transcription factors regulate expression of genes involved in protective biological pathways including those effecting cell metabolism, lipid regulation, redox, and secretory proteostasis. However, despite the efficacy of the UPR in protecting cells against pathologic ER stress, deficiencies in UPR signaling induced by genetic, environmental, or aging-related insults impair the ability of tissues to adapt their physiology, directly contributing to tissue-specific pathologies implicated in many different types of disease. This suggests that selective enhancement of adaptive, protective UPR signaling represents a potential opportunity to mitigate ER stress-associated pathologies implicated in aging and age-related diseases. Consistent with this, genetic, chemical biologic, and in vivo evidence shows that enhancing protective IRE1/XBP1s or ATF6 signaling corrects tissue-specific pathologies implicated in many different maladies. We hypothesize that selective, pharmacological activation of protective IRE1/XBP1s or ATF6 signaling represents a promising therapeutic strategy to mitigate pathologies in aging and numerous age-related diseases. Over the previous funding period, we leveraged cell-based phenotypic high throughput screening (HTS) and whole cell transcriptional profiling to establish first-in-class compounds that selectively activate the adaptive IRE1/XBP1s or ATF6 transcriptional signaling programs. These compounds are being used by our lab and >30 labs around the world to define the functional implications and therapeutic potential of pharmacological IRE1/XBP1s or ATF6 activation in age-associated diseases including protein misfolding disorders, ischemia/reperfusion injury, eye diseases, obesity-diabetes, cancer, and neurodegenerative disorders such as Alzheimer’s disease (AD). Here, we expand this study to establish next generation compounds that selectively activate these protective UPR pathways, through defined mechanisms of action and with improved potency, efficacy, and pharmacodynamic and pharmacokinetic profiles, to increase their application across diverse experimental and disease models. Further, we define the potential for these compounds to enhance memory in mouse models of aging and AD, revealing new opportunities to ameliorate defects in cognitive function through pharmacologic UPR activation.