3-Ethoxy-5,6-dibromosalicylaldehyde

3-Ethoxy-5,6-dibromosalicylaldehyde is an IRE1/ERN1 inhibitor, with an IC₅₀ of 0.12 μM, a K_i of 71-88 nM, and a K_d of 100 nM against the ribonuclease activity of hIRE1α, as well as an IC₅₀ of 4.8 μM against yeast Ire1. It shows selectivity toward IRE1 ribonuclease. 3-Ethoxy-5,6-dibromosalicylaldehyde blocks the IRE1/ERN1-mediated unfolded protein response (UPR) signaling pathway, including XBP-1 mRNA splicing, induction of XBP1 target genes, and activation of MAPK8/9/10, but does not alter the phosphorylation level of IRE1α or the PERK/ATF6 pathway. 3-Ethoxy-5,6-dibromosalicylaldehyde inhibits chikungunya virus replication, induces growth arrest, apoptosis and clonogenic inhibition in pancreatic cancer cells, reduces FB1 (Fumonisin B1) (HY-N6719)-induced autophagy and cell death, regulates PGG-induced senescence and apoptosis, and alleviates Sorafenib (HY-10201)-induced vacuolization and damage in hepatic stellate cells. 3-Ethoxy-5,6-dibromosalicylaldehyde can be used in research related to chikungunya virus infection, pancreatic cancer, FB1-induced nephrotoxicity, liver cancer, breast cancer, lung cancer and liver fibrosis^{[1][2][3][4][5][6][7][8]}. IC50 & Target:IC₅₀s: ∼0.12 μM for hIRE1α-cyto; 6 μM for yeast Ire1^[1] In Vitro:3-Ethoxy-5,6-dibromosalicylaldehyde (DBSA) (30 μM; 4-48 h) inhibits the IRE1 pathway in HEK293 cells, as shown by reduced Xbp1s gene expression and phospho-IRE1 protein levels when used at 30 μM for 4 h (with Tunicamycin (HY-A0098)) or 48 h (with chikungunya virus)^[1].
3-Ethoxy-5,6-dibromosalicylaldehyde (30 μM; 48 h post-infection) suppresses chikungunya virus replication in HEK293 cells when used at 30 μM for 48 h post-infection, as shown by reduced viral E1 gene and protein expression^[1].
3-Ethoxy-5,6-dibromosalicylaldehyde (3ETH) (1 nM-100 μM) inhibits proliferation of a panel of human pancreatic cancer cell lines with IC₅₀ values ranging from 0.4 μM to 76.2 μM, and is active against HNA-resistant cell lines including AsPc1, BxPc3, and PL45^[2].
3-Ethoxy-5,6-dibromosalicylaldehyde (1-10 μM; 14 days) inhibits clonogenic growth of MiaPaCa2 and Panc0403 human pancreatic cancer cells in soft agar^[2].
3-Ethoxy-5,6-dibromosalicylaldehyde (1 μM; 24 hours) up-regulates TXNIP mRNA and down-regulates TXN mRNA in Panc0403 and MiaPaCa2 human pancreatic cancer cells^[2].
3-Ethoxy-5,6-dibromosalicylaldehyde (60 μM; 24 h) suppresses PGG-induced senescence-like growth arrest in HepG2, MCF-7, and A549 cells, as shown by reduced SA-β-gal-positive cell percentages^[5].
3-Ethoxy-5,6-dibromosalicylaldehyde (100 nM-20 μM; 3 min) binds directly and selectively to purified human IRE1α-cyto with a K_d of ~100 nM, and does not bind to RNase A^[6].
Pre-treatment of LX2 and HSC-T6 hepatic stellate cells with 3-Ethoxy-5,6-dibromosalicylaldehyde (10 μM; 60 min pre-incubation prior to 12-24 h Sorafenib treatment) reduces and delays Sorafenib-induced cytoplasmic vacuolation^[7].
3-Ethoxy-5,6-dibromosalicylaldehyde potently and selectively inhibits the endoribonuclease activity of human and yeast IRE1α without affecting autophosphorylation, blocks chemically induced XBP1 splicing and XBP1 target gene induction in cultured cell lines, and binds specifically, reversibly, and dose-dependently to IRE1α^[3].
3-Ethoxy-5,6-dibromosalicylaldehyde potently inhibits the endoribonuclease activity of purified human IRE1α-cyto with an IC₅₀ of ~0.12 μM via a non-competitive mechanism relative to the mini-XBP-1 RNA substrate^[6].
3-Ethoxy-5,6-dibromosalicylaldehyde (0.48-60 μM; 1 h) inhibits yeast Ire1 endoribonuclease activity with an IC₅₀ of 6 μM, which is 50-fold less potent than its activity against human IRE1α-cyto^[6].
3-Ethoxy-5,6-dibromosalicylaldehyde (5-120 μM; 2 h) dose-dependently inhibits DTT (DL-Dithiothreitol) (HY-15917)-induced XBP-1 splicing in human MM1.s myeloma cells, with complete inhibition at high concentrations^[6].
Pre-treatment of LX2 and HSC-T6 hepatic stellate cells with 3-Ethoxy-5,6-dibromosalicylaldehyde (EDBS) (10 μM; 60 min pre-incubation prior to 12-24 h Sorafenib treatment) suppresses Sorafenib-induced activation of the IRE1α-XBP1s ER stress/UPR pathway by reducing protein expression of IRE1α, GRP78, XBP1s, and calreticulin^[7].
3-Ethoxy-5,6-dibromosalicylaldehyde directly inhibits IRE1α endoribonuclease activity by covalently binding to lysine K907, dose-dependently reducing Xbp1 splicing in human cell lines without altering other UPR pathways^[8].
3-Ethoxy-5,6-dibromosalicylaldehyde (DBS) (50 μM; 48 h) inhibits FB1-induced MAPK8/9/10 activation, autophagy, and subsequent cell death in MARC-145 monkey kidney cells^[4].
3-Ethoxy-5,6-dibromosalicylaldehyde (60 μM; 24 h) inhibits PGG-induced autophagosome formation in HepG2 cells, as indicated by a reduced LC3-II/ACTB ratio of 0.08 compared to 0.36 with PGG alone^[5].
3-Ethoxy-5,6-dibromosalicylaldehyde (24 h) enhances PGG-induced cell death in HepG2 and MCF-7 cells after 48 h of combined treatment^[5].
Pre-treatment of LX2 hepatic stellate cells with 3-Ethoxy-5,6-dibromosalicylaldehyde (10 μM; 60 min pre-incubation prior to 12-24 h Sorafenib treatment) drastically reduces Sorafenib-induced non-apoptotic cell death at 12 h and 24 h post-treatment^[7]. In Vivo:3-Ethoxy-5,6-dibromosalicylaldehyde (3ETH) (20 mg/kg; i.p.; three times weekly; 4 weeks) reduces BxPc3 human pancreatic cancer xenograft growth in NOD/SCID mice, with treated tumors weighing 70% of control tumors^[2].