ISRIB (short for "integrated stress response inhibitor") is an experimental tool compound that blocks the integrated stress response, restoring the cell’s translation capacity.[1] It showed promising results in mouse models of brain disorders but efforts to develop a drug based on it, had failed as of 2025.
 | |
| Clinical data | |
|---|---|
| ATC code |
|
| Pharmacokinetic data | |
| Elimination half-life | 8 h |
| Identifiers | |
| |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| UNII | |
| CompTox Dashboard (EPA) | |
| Chemical and physical data | |
| Formula | C22H24Cl2N2O4 |
| Molar mass | 451.34 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
Discovery
editIt was discovered by Carmela Sidrauski 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 seeking inhibitors of PERK signalling; it was found to block the integrated stress response when measured by eIF2α phosphorylation with an IC50 of 5 nM.[2][3] It has been shown to inhibit eIF2α phosphorylation-induced stress granule (SG) formation.[4]
Mechanism of action
editCryo-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.[5]
Preclinical work
editTesting 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.[2]
Testing of ISRIB in 2017 indicated improved the ability of brain-injured mice to learn and form memories on memory tests, thus appearing to reverse impairments from traumatic brain injury.[6][7] ISRIB treatment also corrects spatial memory deficits and improves working memory in aged mice.[8]
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.[3]
Further refinement and clinical development
editThe technology was licensed to Calico in 2015 and Sidrauski was hired to help find possible drugs based on ISRIB.[3] She heads the laboratory in which it is being studied.
Calico partnered with Abbvie to create fosigotifator based on ISRIB and the companies began to develop fosigotifator for amyotrophic lateral sclerosis (ALS) and major depressive disorder.[9][10] In January 2025 Abbott and Calico announced that the drug had failed a Phase 2/3 trial in ALS; in July 2025 Abbott ended its partnership with Calico.[9]
See also
editReferences
edit- ^ Hanson FM, Hodgson RE, de Oliveira MI, Allen KE, Campbell SG (June 2022). "Regulation and function of elF2B in neurological and metabolic disorders". Bioscience Reports. 42 (6). doi:10.1042/BSR20211699. PMC 9208314. PMID 35579296.
- ^ a b Sidrauski C, Acosta-Alvear D, Khoutorsky A, Vedantham P, Hearn BR, Li H, et al. (May 2013). "Pharmacological brake-release of mRNA translation enhances cognitive memory". eLife. 2 e00498. doi:10.7554/eLife.00498. PMC 3667625. PMID 23741617.
- ^ a b c Piore A (August 25, 2021). "The miracle molecule that could treat brain injuries and boost your fading memory". MIT Technology Review.
Carmela Sidrauski interview
- ^ Sidrauski C, McGeachy AM, Ingolia NT, Walter P (February 2015). "The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly". eLife. 4 e05033. doi:10.7554/eLife.05033. PMC 4341466. PMID 25719440.
- ^ Anand AA, Walter P (January 2020). "Structural insights into ISRIB, a memory-enhancing inhibitor of the integrated stress response". The FEBS Journal. 287 (2): 239–245. doi:10.1111/febs.15073. PMID 31550413.
- ^ Cross R (July 11, 2017). "Memory-enhancing drug reverses effects of traumatic brain injury in mice". Science. American Association for the Advancement of Science. Retrieved July 12, 2017.
- ^ Gallegos J (2017-07-10). "New drug restores memories in brain-damaged mice". Washington Post. ISSN 0190-8286. Retrieved 2018-06-27.
- ^ Krukowski K, Nolan A, Elma S, Frias E, Boone M, Ureta G, et al. (December 2020). "Small molecule cognitive enhancer reverses age-related memory decline in mice". eLife. 9 e62048. doi:10.7554/eLife.62048. PMC 7721440. PMID 33258451. This article incorporates text from this source, which is available under the CC BY 4.0 license.
- ^ a b "Fosigotifator". alzforum.org. 21 Nov 2025. Retrieved 24 November 2025.
- ^ Masson G (13 November 2025). "AbbVie to end Calico collab, lays off researchers: Stat". www.fiercebiotech.com. Retrieved 24 November 2025.