12fh | pdb_000012fh
Structure of eIF2B bound to a activator
Structural highlights
DiseaseEI2BD_HUMAN Juvenile or adult CACH syndrome;Congenital or early infantile CACH syndrome;Cree leukoencephalopathy;Late infantile CACH syndrome;Ovarioleukodystrophy. The disease is caused by mutations affecting the gene represented in this entry. FunctionEI2BD_HUMAN Catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. Publication Abstract from PubMedThe integrated stress response (ISR) is a highly conserved cellular pathway triggered by a variety of insults, reducing protein synthesis and inducing ATF4, leading to broadly remodeling the cellular transcriptome and metabolome. ISRIB, 1, the first identified eIF2B activator, attenuates the ISR restoring protein synthesis, but its poor solubility limits absorption and advancement. To improve drug-like properties, we explored replacements for both the cyclohexyl core and side chains of ISRIB. This effort initially led to truncated analogue, 2BAct, 13, which demonstrated improved solubility relative to 1; however, cardiovascular effects in higher species limited its progression into the clinic. Potent analogue 9 was identified with significantly improved solubility vs 1 but was still projected to have solubility-limited absorption. A prodrug campaign resulted in the identification of compound 26 (fosigotifator), which exhibited significantly improved solubility and is currently being investigated in the clinic. Discovery of Fosigotifator, a Potent eIF2B Activator with Desired Properties for Human Studies.,Frost JM, Tong Y, Xu X, Shi L, Pliushchev M, Murauski KJ, Kohlhaas K, Donnelly-Roberts DL, Sheehan MM, Riedmaier S, Oberoi HS, Chen J, Prakash J, Hutchins CW, Jakob CG, Jain R, Qiu W, Henry RF, Edalji R, Sun C, Carr T, Basso AM, Brown BS, Voight EA, Sidrauski C, Dart MJ J Med Chem. 2026 May 19. doi: 10.1021/acs.jmedchem.6c00716. PMID:42153306[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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