Eukaryotic Initiation Factor (eIF) Activator

2BAct is a highly selective, orally active, and CNS-penetrant eIF2B (eukaryotic initiation factor 2B) activator with an EC₅₀ of 33 nM. 2BAct prevents neurological defects caused by a chronic integrated stress response. 2BAct displays improved solubility and pharmacokinetics relative to eIF2B activator ISRIB trans-isomer (HY-12495).

Necrocide 1, a necrosis by sodium overload (NECSO) inducer, is a selective transient receptor potential melastatin 4 (TRPM4) agonist with an EC₅₀ of 306.3 nM for human TRPM4. Necrocide 1 triggers TRPM4-dependent necrotic cell death through the induction of sodium influx. Necrocide 1 induces hallmarks of immunogenic cell death incurring calreticulin (CALR) exposure, ATP secretion and high mobility group box 1 (HMGB1) release. Necrocide 1 can be used for the study of breast and prostate cancer.

L-Azetidine-2-carboxylic acid is a proline analog. L-Azetidine-2-carboxylic acid upregulates the lipid autophagy marker LC3-II via activation of the PERK pathway. L-Azetidine-2-carboxylic acid increases pro-apoptotic BAX protein. L-Azetidine-2-carboxylic acid induces ATF6 cleavage and upregulates phosphorylated eIF2α levels. L-Azetidine-2-carboxylic acid induces ER stress, inducing protein misfolding and aggregation. L-Azetidine-2-carboxylic acid shows teratogenic, pro-inflammatory and pro-apoptotic effects.

ATF4-IN-1 (Compound 21) is an ATF4 inhibitor and also an eIF2B activator. ATF4-IN-1 can be used in research on neurodegenerative diseases.

DNL343 is a potent, selective, orally active and brain-penetrant activator of eukaryotic initiation factor eIF2B. DNL343 inhibits the activity of the integrated stress response (ISR) in the central nervous system (CNS) and reverses neurodegeneration and neuroinflammation. DNL343 also prevents motor dysfunction and premature death in eIF2B loss-of-function (LOF) mutant mice. DNL343 can be used in the study of neurodegenerative diseases.

Kurarinone is an orally active flavonoid isolated from matrine that inhibits the pathogenesis of experimental autoimmune encephalomyelitis by inhibiting cell differentiation of Th1 and Th17. Kurarinone has antitumor and anti-inflammatory activity.

HR-19011 is an eIF2α phosphorylation activator targeting heme-regulated inhibitor HRI (EIF2AK1). HR-19011 exhibits growth inhibitory activity against K562 cells with an IC₅₀ value of 3.91 µM. HR-19011 inhibits the growth of hematologic malignancies by targeting HRI to activate the integrated stress response via the HRI-eIF2α-ATF4 axis. HR-19011 shows good safety in vivo. HR-19011 can be used for research on hematologic malignancies (leukemia).

E235 is an expression regulator of activates transcription factor 4 (ATF4). E235 reduces cell viability by activating integrated stress response (ISR) and DNA damage response signals. E235 has anti-proliferative activity and can be used for tumor research.

Palladium(II) acetylacetonate is a metal-organic complex. Palladium(II) acetylacetonate upregulates the expression of GRP78, ATF-4, XBP-1, CHOP, and phosphorylated c-Jun. Palladium(II) acetylacetonate induces Apoptosis. Palladium(II) acetylacetonate has anticancer effects against non-small cell lung cancer, gastric cancer, leukemia, and cervical cancer.

EIF2α activator 2 (Compound 1) is an activator of eukaryotic initiation factor 2 alpha (eIF2α) phosphorylation. EIF2α activator 2 exhibits high potency in SRB cell proliferation assays (IC₅₀=0.46 μM). EIF2α activator 2 exhibits antiproliferative activity againist K562 and PBMC cells with IC₅₀s of 4.79 and 10.52 μM, respectively.

1,2,4-Trihydroxybenzene (Hydroxyhydroquinone) is an ER stress inducer that targets proteins such as PKR-like ER kinase PERK to induce cytotoxicity. 1,2,4-Trihydroxybenzene selectively activates eIF2α phosphorylation, activates the PERK-eIF2α signaling pathway and induces stress granule formation. 1,2,4-Trihydroxybenzene subsequently exacerbates oxidative stress and causes DNA double-strand breaks, destroying organelles such as mitochondria and ER, and inducing cell death. 1,2,4-Trihydroxybenzene also has the potential to exhibit anti-tumor effect, increase blood pressure, and relieve spasm.

ML291 is a UPR (unfolded protein response)-inducing sulfonamidebenzamide. ML291 overwhelms the adaptive capacity of the UPR and induces apoptosis in a variety of solid cancer models. ML291 can activate the PERK/eIF2a/CHOP (apoptotic) arm of the UPR and reduce leukemic cell burden.

Fosigotifator (ABBV-CLS-7262) THAM sodium is a brain penetrant, orally active EIF2b (eukaryotic initiation factor) activator. Fosigotifator THAM sodium stabilizes the elF2B complex and boosts the activity, including that of complexes carrying pathogenic vanishing white matter (VWM) mutations. Fosigotifator THAM sodium is an integrated stress response inhibitor (ISRI). Fosigotifator THAM sodium can be used for amyotrophic lateral sclerosis research.

IDB-001 is a human ribosomal peptidyl transferase center (PTC) inhibitor that induces conformational changes and blocks translational elongation in specific sequence contexts through complementary interactions with Asp/Glu residues in nascent polypeptides. IDB-001 preferentially stalls ribosomes at positions containing acidic peptide motifs, thereby inhibiting cancer cell proliferation, and activates the integrated stress response via eIF2α phosphorylation at high concentrations. In addition, IDB-001 mildly triggers ribotoxic stress responses through phosphorylation of JNK and p38. IDB-001 has been applied to mechanistic studies of triple-negative breast cancer.

Fosigotifator (ABBV-CLS-7262) is a brain penetrant, orally active EIF2b (eukaryotic initiation factor) activator. Fosigotifator stabilizes the elF2B complex and boosts the activity, including that of complexes carrying pathogenic vanishing white matter (VWM) mutations. Fosigotifator is an integrated stress response inhibitor (ISRI). Fosigotifator can be used for amyotrophic lateral sclerosis research.

ISR activator 2 is a selective ISR activator. ISR activator 2 can preferentially activate the ISR through the binding of the cytosolic pattern recognition receptor RIG-I, which subsequently activates the heme-regulated inhibitor (HRI) ISR kinase independent of an interferon response. ISR activator 2 can be used for the study of pancreatic cancer.

1,3-Bis[3,5-bis(trifluoromethyl)phenyl]urea is a potent activator of eIF2α kinase heme regulated inhibitor. 1,3-Bis[3,5-bis(trifluoromethyl)phenyl]urea reduces the abundance of eIF2·GTP·tRNA_i^Met ternary complex. 1,3-Bis[3,5-bis(trifluoromethyl)phenyl]urea inhibits cancer cell proliferation.

ZNL-02-096 is a selective Wee1 PROTAC degrader. ZNL-02-096 binds to CRBN and Wee1 to form a ternary complex, inducing CRBN- and proteasome-dependent ubiquitination and proteasomal degradation of Wee1. ZNL-02-096 inhibits recombinant PLK1 with an IC₅₀ of 102 nM, but does not induce its degradation in cells. ZNL-02-096 induces G₂/M phase arrest, Apoptosis, transient integrated stress response, upregulation of ATF4, and phosphorylation of GCN2. ZNL-02-096 reduces Tyr15 phosphorylation of CDK1. ZNL-02-096 can be used in research related to ovarian cancer, acute lymphoblastic leukemia, triple-negative breast cancer, multiple myeloma, and pancreatic ductal adenocarcinoma.

eIF2B activator-1 (Compound 7a) is a eIF2B activator with a pEC₅₀ value of 7.3. eIF2B activator-1 exhibits significant hERG inhibitory activity, with a pIC₅₀ value of 5.7. eIF2B activator-1 can be used in research related to Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS).

ISR activator 3 (Compound cc81) is the active metabolite of A8. ISR activator 3 activates the integrated stress response (ISR) by binding to RIG-I (K_D ≈ 0.55 μM), without inducing lipid droplet clearance. ISR activator 3 enhances the interferon response under viral mimicry signals. ISR activator 3 can be used for research on neurodegenerative diseases and immune stress.