thapsigargin

Thapsigargin is a natural product, an inhibitor of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) and an endoplasmic reticulum stress inducer. Thapsigargin increases cytoplasmic calcium concentration by blocking the ability of cells to pump calcium into the sarcoplasmic and endoplasmic reticulum.

Pyr6 (N-[4-[3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-3-fluoro-4-pyridinecarboxamide) is a selective TRPC3 inhibitor with IC50 of 0.49 uM(Ca2+ influx inhibition in thapsigargin depleted native RBL-2H3 cells).Pyr6 is an inhibitor of Ca2+ entry, which displays higher potency to inhibit Ca2+ entry mediated by CRAC channel than by TRPC3.

FKGK 18 is an inhibitor of group VIA (GVIA) calcium-independent phospholipase A2 (iPLA2). It inhibits GVIA iPLA2 by 99.9% at 0.091 mole fraction in a mixed micelle activity assay and is selective for GVIA iPLA2 over GIVA cPLA2 and GV sPLA2 where it shows 80.8 and 36.8% inhibition, respectively. FKGK 18 inhibits iPLA2β activity in cytosolic extracts from INS-1 cells overexpressing iPLA2β (IC50 = ~50 nM) as well as iPLA2γ activity in mouse heart membrane fractions (IC50s = ~1-3 μM). It inhibits glucose-induced increases in prostaglandin E2 production and insulin secretion in human pancreatic islets when used at a concentration of 10 μM and inhibits thapsigargin-induced apoptosis in INS-1 cells overexpressing iPLA2β in a concentration-dependent manner. FKGK 18 (20 mg/kg, 3 times per week) reduces blood glucose levels in an intraperitoneal glucose tolerance test, decreases the incidence of diabetes, and increases serum insulin levels in non-obese diabetic (NOD) mice.

Trilobolide is a natural counterpart of thapsigargin and an activator of cytokine secretion.

Azumolene sodium anhydrous is a muscle relaxant that inhibits the release of calcium from skeletal muscle sarcoplasmic reticulum. Azumolene inhibits a component of store-operated calcium entry coupled to the skeletal muscle ryanodine receptor. Azumolene, an equipotent dantrolene analog, inhibits a component of SOCE coupled to activation of RyR1 by caffeine and ryanodine, whereas the SOCE component induced by thapsigargin is not affected.

Soluble epoxide hydrolase (sEH) PROTAC 1a is a proteolysis-targeting chimera (PROTAC) comprising a cereblon ligand linked to the sEH inhibitor t-TUCB via a linker, promoting selective sEH degradation and inhibiting its hydrolase activity (IC50 = 0.8 nM) significantly more than its phosphatase activity (IC50 = >10,000 nM). This compound preferentially targets cytosolic sEH for lysosomal rather than proteasomal degradation. Furthermore, it mitigates thapsigargin-induced upregulation of phosphorylated inositol-requiring enzyme 1α (IRE1α) and X-box binding protein 1 (XBP1) splicing in HepG2 and 293T cells, thereby reducing endoplasmic reticulum stress.

ATF4-IN-1 (Compound 21) serves as an inhibitor of ATF4, demonstrating effective suppression of ATF4 expression in Thapsigargin-stimulated HEK-293T cells with an IC50 of 32.43 nM. Compared to ISRIB, ATF4-IN-1 shows enhanced activity and exhibits minimal cytotoxicity, with an IC50 of 96 μM in HEK-293T cells. This compound is utilized in the investigation of neurodegenerative diseases [1].