eIF2 Inhibitor

GCN2-IN-1 is a potent general control nonderepressible 2 kinase (GCN2) inhibitor with an IC₅₀ of <0.3 μM in the enzyme assay and an IC₅₀ of 0.3-3 μM in the cell assay.

GCN2-IN-6 (Compound 6d) is a potent, and orally available GCN2 inhibitor confirmed by in-house enzymatic (IC₅₀ of 1.8 nM) and cellular assays (IC₅₀ of 9.3 nM). GCN2-IN-6 is also a eIF2α kinase PERK inhibitor with an IC₅₀ of 0.26 nM (in enzymatic assay) and 230 nM (in cells). GCN2-IN-6 is a click chemistry reagent, it contains an Alkyne group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing Azide groups.

APL-4098 is an orally active, selective, ATP-competitive GCN2 inhibitor with a K_i of 4.39 nM and a K_d of 2.9 nM. APL-4098 reduces the phosphorylation level of eIF2α and the expression level of ATF4. APL-4098 impairs mitochondrial function and exerts cytotoxic effects on primary acute myeloid leukemia cells. APL-4098 is applicable to research related to acute myeloid leukemia.

ISR-IN-1 is an integrated stress response (ISR) inhibitor targeting eIF2B. ISR-IN-1 enhances eIF2B guanine nucleotide exchange factor activity, stabilizes eIF2B heteropentamer dimers via symmetrical protein-protein interface binding, and releases global protein synthesis inhibition from phosphorylated eIF2α^α. ISR-IN-1 can be used for the research of prion disease.

GCN2 activator-1 (Compound 20) is a GCN2 activator. GCN2 activator-1 binds within the ATP-pocket of GCN2 and activates GCN2 in a GCN1-independent manner. GCN2 activator-1 activates Integrated Stress Response (ISR) in cells. GCN2 activator-1 inhibits PKR with an IC₅₀ of 3.75 µM. GCN2 activator-1 can be used for research of pulmonary veno-occlusive disease (PVOD).

OICR-403184 is a selective RNA-dependent protein kinase (PKR) inhibitor with limited brain penetration, with an IC₅₀ of 263 nM. OICR-403184 blocks the phosphorylation of eIF2α downstream of PKR. OICR-403184 is applicable to the research of inflammatory bowel disease.