ISRIB

ISRIB (integrated stress response inhibitor) is an experimental drug that reverses the effects of eIF2α phosphorylation with an IC50 of 5 nM. It was discovered in the laboratory of Peter Walter at University of California, San Francisco (UCSF) through a semi-automated screening of a large library of small molecules by Carmela Sidrauski, who decided to pursue research on it. It has been shown to inhibit eIF2α phosphorylation-induced stress granule (SG) formation. Since eIF2α phosphorylation is known to be involved in memory formation, ISRIB was tested to see whether it would be active in vivo, and was found to readily cross the blood–brain barrier, with a half-life of eight hours.

Drug development
Subsequent testing in 2013 found ISRIB to produce significant nootropic effects in mice, as measured by enhancement of spatial and fear-associated learning in standard water-maze and conditioned environment tests.

The technology was licensed to Calico in 2015 and Sidrauski was hired to help find possible drugs based on ISRIB. She heads the laboratory in which it is being studied.

Testing in 2017 indicated the experimental drug improved the ability of brain-injured mice to learn and form memories on memory tests, thus appearing to reverse impairments from traumatic brain injury. ISRIB treatment also corrects spatial memory deficits and improves working memory in aged mice.

Further research on the drug by Sidrauski has shown that the molecule restored memory formation in mice months after traumatic brain injuries. It also has shown potential in treating neurodegenerative diseases such as Alzheimer's, Parkinson's, and Lou Gehrig's disease (also known as amyotrophic lateral sclerosis, or ALS). In mice, it has reduced age-related cognitive decline and given healthy mice improved memory. Research on ISRIB by Sidrauski continues at Calico.

Mechanism of action
Cryo-EM structures of ISRIB bound to eIF2B indicates that ISRIB staples together two tetrameric eIF2B (βγδε) subcomplexes into a 8-meric complex (βγδε)2, which is more amenable to binding EIF2B alpha subunits. As a result, ISRIB accelerates the assembly of EIF2B into an active 10-meric form, thereby increasing the amount of active EIF2B. Because phosphorylation of eIF2α exerts its effects by depleting the stock of active EIF2B, increasing the EIF2B supply would reverse its effects. ISRIB does not increase the total supply of EIF2B, so in cell cultures with very high levels of stress, the ISR can still proceed after the inactivating the cell's entire stock of EIF2B.