12FH

Structure of eIF2B bound to a activator

This is a non-PDB format compatible entry.

Summary for 12FH

• Entry DOI: 10.2210/pdb12fh/pdb
• Descriptor: Isoform 2 of Translation initiation factor eIF2B subunit delta, Translation initiation factor eIF2B subunit beta, unidentified protein fragment, ... (6 entities in total)
• Functional Keywords: guanine nucleotide exchange factor, translation initiation, protein complex, sugar binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 203396.45

Authors

Jain, R.,Jakob, C.G.,Qiu, W. (deposition date: 2026-04-01, release date: 2026-06-03)

Primary citation

Frost, J.M.,Tong, Y.,Xu, X.,Shi, L.,Pliushchev, M.,Murauski, K.J.,Kohlhaas, K.,Donnelly-Roberts, D.L.,Sheehan, M.M.,Riedmaier, S.,Oberoi, H.S.,Chen, J.,Prakash, J.,Hutchins, C.W.,Jakob, C.G.,Jain, R.,Qiu, W.,Henry, R.F.,Edalji, R.,Sun, C.,Carr, T.,Basso, A.M.,Brown, B.S.,Voight, E.A.,Sidrauski, C.,Dart, M.J.
Discovery of Fosigotifator, a Potent eIF2B Activator with Desired Properties for Human Studies.
J.Med.Chem., 2026

PubMed Abstract: The 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, , 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, , which demonstrated improved solubility relative to ; however, cardiovascular effects in higher species limited its progression into the clinic. Potent analogue was identified with significantly improved solubility vs but was still projected to have solubility-limited absorption. A prodrug campaign resulted in the identification of compound (fosigotifator), which exhibited significantly improved solubility and is currently being investigated in the clinic.

PubMed: 42153306
DOI: 10.1021/acs.jmedchem.6c00716

Experimental method

X-RAY DIFFRACTION (3.5 Å)