Activation of this stress-signaling pathway can alter the fate of diseased cells. On one hand, it can be co-opted by cancer cells to sustain survival in the face of continuous stresses imposed by genomic instability and high mutational rates. On the other hand, as in type 2 diabetes, inherited protein folding and neurodegenerative diseases, its sustained activation can trigger apoptotic pathways leading to neuronal loss. To dissect the role of each of the UPR branches (IRE1, PERK and ATF6) in disease progression, we seek to identify tool compounds that specifically and acutely block each signaling arm. The discovery and development of these novel molecules will allow us to carefully assess the contribution of the different stress signaling branches to disease progression.
We have implemented cell-based screens to identify small molecule modulators. These screens have yielded potent and specific molecules that modulate each one of the branches of the UPR. We are currently focusing on a unique and potent tool compound, ISRIB, that not only blocks the PERK branch of the UPR but is an integrated stress response (ISR) inhibitor acting downstream of all eIF2 kinases (PERK, GCN2, HRI and PKR). Acute pharmacological treatment with ISRIB enhances cognition in normal rodents. We are now testing whether chronic inhibition of the ISR can prevent or reverse the cognitive decline that is associated with various neurodegenerative diseases. We are also focusing our efforts on a novel ATF6 signaling inhibitor. Chemistry efforts are geared towards improving its pharmacokinetic properties to test its effects in vivo. Our goal is to identify the target of these novel molecules in cells, dissect the molecular mechanisms by which they block their respective signaling pathways, and explore if we can identify a therapeutic window for them in disease models.
Besides the unbiased small molecule cell-based screens, we have also rationally designed modulators (ATP mimetics) that bind the kinase domain of IRE1 and positively or negatively modulate its RNAse activity. We investigate the mechanism by which occupancy of the ATP binding pocket results in activation or inhibition of the RNase function using enzymological and structural techniques. By using these tool compounds, we seek to understand the regulation of the two different outputs of the RNAse domain: the highly specific splicing of the XBP1 mRNA substrate and the degradation of ER-localized mRNAs. (RIDD).