Discovering Small Molecule Activators of Stress-responsive Signaling

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The maintenance of secreted protein homeostasis, or proteostasis, involves balancing protein biosynthesis, translocation across membranes, folding, degradation, etc., which we hypothesize is critical for healthy aging. Since the demands on secretory compartments to maintain proteostasis change with development, aging, and environmental stresses, mammals evolved the Unfolded Protein Response (UPR) stress-responsive signaling pathway, which transcriptionally adjusts secretory proteostasis network capacity to meet demand. Recent human genetic, chemical biologic, and in vivo evidence shows that activating the protective IRE1/XBP1s or ATF6 arms of the UPR has significant promise to ameliorate age-related declines in secretory proteostasis and correct imbalances associated with etiologically-diverse diseases, including systemic amyloid diseases, cardiovascular disorders, diabetes, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Few compounds exist to achieve arm-selective UPR activation, and those that do suffer from limitations that prevent their translational development. We have leveraged cell-based transcriptional reporter assays miniaturized for high-throughput screening (HTS), along with whole cell transcriptional and proteomic profiling to understand the selectivity of the transcriptional and translational response generated by our screening hits. We have elaborated promising compounds using medicinal chemistry to establish first-in- class small molecule `proteostasis regulators' that selectively activate the protective IRE1/XBP1s or ATF6 signaling arms of the UPR with improved potency and selectivity, and we seek their mechanism of action through multiple approaches. We will assess whether our proteostasis regulators can induce protective, arm- selective UPR activation in young and old animals. We have established collaborations to test the hypothesis that our IRE1/XBP1s and ATF6 activators will be useful for ameliorating pathologic imbalances in secretory proteostasis associated with multiple diseases, including the systemic amyloidoses, degenerative eye diseases, cardiovascular disease, and neurodegenerative disorders. Furthermore, we will show that these compounds pharmacologically ameliorate two pathologic phenotypes associated with Alzheimer's disease in cell culture models: i.e., the pathologic production of Aβ and Aβ oligomer-associated neuronal cytotoxicity. We will deliver to the scientific community the first well-characterized small molecules that preferentially activate the IRE1/XBP1s or the ATF6 UPR transcriptional programs with a defined potency and selectivity. These compounds have the potential to be widely employed as therapeutics for a spectrum of age-associated diseases. Importantly, these compounds will be made available to all scientists with disease models wherein pharmacologic IRE1/XBP1s or ATF6 activation has the potential to influence pathogenesis. The availability of these compounds offers the promise to broadly influence multiple aspects of scientific endeavor funded by the NIH, including basic science such as stem cell biology.