unfolded protein response

Azoramide, a small-molecule modulator, has the antidiabetic activity of unfolded protein response.

Ceapin-A7, with an IC50 of 0.59 μM, selectively inhibits ATF6α signaling in response to ER stress. This compound is instrumental in investigating ATF6α's activation mechanism and its function in pathological conditions.

IXA4 is a highly selective, nontoxic activator of IRE1/XBP1s and reduces APP secretion by activating IRE1. IXA4-stimulated IRE1 activation also enhanced pancreatic function.

ErSO is a selective activator of anticipatory unfolded protein response (UPR) via ERα receptor. ErSO can be used in studies about anti-cancer.

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.

CCI-006, a selective inhibitor and chemosensitizer for MLL-rearranged leukemia cells, disrupts mitochondrial respiration. This action leads to irreversible mitochondrial depolarization and triggers a pro-apoptotic unfolded protein response in specific MLL-r leukemia cells.

RA-9 is a potent and selective proteasome-associated inhibitor of deubiquitinating enzymes (DUBs) with a favorable toxicity profile and anticancer activity, particularly effective in inducing apoptosis in ovarian cancer cell lines.

3,6-DMAD hydrochloride functions as an inhibitor for the IRE1α-XBP1 pathway within the unfolded protein response mechanism.

AA147 (ATF6-activator-147) is a small molecule endoplasmic reticulum (ER) proteostasis regulator. The selectively activates ATF6 arm of the unfolded protein response (UPR) .It acts as a prodrug that preferentially triggers ATF6 signaling through a mechanism involving localized metabolic activation and selective covalent modification of ER resident proteins that regulate ATF6 activity.

BHPI is a potent inhibitor of nuclear estrogen receptor ERα–regulated gene expression that induces sustained ERα-dependent activation of the endoplasmic reticulum stress sensor and unfolded protein response, leading to persistent inhibition of protein synthesis, and in ERα-positive cancer cells it hyperactivates plasma membrane PLCγ to generate IP3, deplete ER calcium stores via IP3R channels, and convert the normally protective UPR into a toxic response, making BHPI a valuable probe for estrogen signaling and ER stress–based cancer research.

DIM-C-pPhtBu is an orally active endoplasmic reticulum stress activator. It induces mitochondrial and lysosomal dysfunction, excessive mitosis, ROS production, and cell death mediated by the unfolded protein response in cervical cancer cells. DIM-C-pPhtBu exhibits antitumor activity.

Autophagyactivator-1 (Compound B2) is an autophagy activator that induces autophagy by downregulating key members of the HSP70 family and activating the unfolded protein response.

DCEM1 binds to heat shock protein 60 (HSP60) and inhibits the interaction between HSP60 and ClpP, thereby blocking the mitochondrial unfolded protein response. Additionally, DCEM1 suppresses the expression of β-catenin and reduces ATP production in PC-3 and TKO cells. It is utilized in research related to prostate cancer.

VCP/p97 IN-3 is an allosteric inhibitor of VCP/p97. It exhibits inhibitory activity against VCP, with an IC50 of 9 nM, and shows IC50 values of 12 nM (N660K) and 19 nM (V474A/D649A) for mutant VCP proteins. VCP/p97 IN-3 increases the levels of K48 ubiquitination and caspase-3. It activates endoplasmic reticulum stress and the unfolded protein response (UPR). In a subcutaneous xenograft mouse model with RPMI-8226 cells, VCP/p97 IN-3 suppresses tumor growth. This compound is applicable for research in multiple myeloma.

Ironomycin is a derivative of Salinomycin. It exhibits selective inhibitory activity against mantle cell lymphoma (MCL) cells. Ironomycin halts the cell cycle and induces apoptosis and ferroptosis. It also causes DNA double-strand breaks and activates the unfolded protein response (UPR), specifically accumulating the IRE1α signaling pathway. Combined use of Ironomycin and Ibrutinib shows a synergistic effect. Ironomycin is useful for MCL research.

AC-45594 is a UPR activator. It induces endoplasmic reticulum stress and activates the unfolded protein response (UPR), promoting the shift from adaptive to terminal stress signaling, ultimately leading to apoptosis (Apoptosis). AC-45594 activates Caspase-3, induces PARP cleavage, and increases DR5 protein levels, selectively inhibiting the growth of Ewing sarcoma cells.

Cytisine-Platinum(IV) Prodrug-1 (CP12) is a Pt(IV) prodrug incorporating the natural product cytisine, known for its antiproliferative effects on tumor cells. CP12 facilitates calcium ion transport via the IP3R1-GRP75-VDAC1 axis, causing mitochondrial calcium overload. It initiates the unfolded protein response through PERK, eIF2α, ATF4, and CHOP, regulating Bcl-2 and Bax to induce apoptosis. Additionally, CP12 leads to mitochondrial dysfunction, reactive oxygen species (ROS) production, reduced ATP synthesis, DNA damage, and S-phase cell cycle arrest. It activates the cGAS-STING pathway, decreases PD-L1 expression, and promotes immunogenic cell death. CP12 exhibits high physiological stability, efficient cellular accumulation, and enhanced platinum-DNA binding capacity, suppressing tumor growth with reduced systemic toxicity in mouse models. This compound is useful for lung cancer research.

ML-291 is a potent inducer of the Unfolded Protein Response (UPR). It triggers apoptosis via the PERK/eIF2α/CHOP arm, used for solid tumor and leukemia research.

UPR-IN-17# is an effective pan-inhibitor of the unfolded protein response.

Nemorosone is a polycyclic polyprenylated acylphloroglucinol (PPAP) originally isolated from C. rosea that has antiproliferative properties.1 Nemorosone inhibits growth of NB69, Kelly, SK-N-AS, and LAN-1 neuroblastoma cells (IC50s = 3.1-6.3 μM), including several drug-resistant clones, but not MRC-5 human embryonic fibroblasts (IC50 = >40 μM).2 It increases DNA fragmentation in LAN-1 cells in a dose-dependent manner, and decreases N-Myc protein levels and phosphorylation of ERK1/2 by MEK1/2. Nemorosone also inhibits growth of Capan-1, AsPC-1, and MIA-PaCa-2 pancreatic cancer cells (IC50s = 4.5-5.0 μM following a 72-hour treatment) but not human dermal and foreskin fibroblasts (IC50s = >35 μM).1 It induces apoptosis, abolishes the mitochondrial membrane potential, and increases cytosolic calcium concentration in pancreatic cancer cells in a dose-dependent manner. Nemorosone activates the caspase cascade in a dose-dependent manner and inhibits cell cycle progression, increasing the proportion of cells in the G0/G1 phase, in both neuroblastoma and pancreatic cancer cells.1,2 Nemorosone (50 mg/kg, i.p., per day) also reduces tumor growth in an MIA-PaCa-2 mouse xenograft model.3References1. Holtrup, F., Bauer, A., Fellenberg, K., et al. Microarray analysis of nemorosone-induced cytotoxic effects on pancreatic cancer cells reveals activation of the unfolded protein response (UPR). Br. J. Pharmacol. 162(5), 1045-1059 (2011).2. Díaz-Carballo, D., Malak, S., Bardenheuer, W., et al. Cytotoxic activity of nemorosone in neuroblastoma cells. J. Cell. Mol. Med. 12(6B), 2598-2608 (2008).3. Wold, R.J., Hilger, R.A., Hoheisel, J.D., et al. In vivo activity and pharmacokinetics of nemorosone on pancreatic cancer xenografts. PLoS One 8(9), e74555 (2013). Nemorosone is a polycyclic polyprenylated acylphloroglucinol (PPAP) originally isolated from C. rosea that has antiproliferative properties.1 Nemorosone inhibits growth of NB69, Kelly, SK-N-AS, and LAN-1 neuroblastoma cells (IC50s = 3.1-6.3 μM), including several drug-resistant clones, but not MRC-5 human embryonic fibroblasts (IC50 = >40 μM).2 It increases DNA fragmentation in LAN-1 cells in a dose-dependent manner, and decreases N-Myc protein levels and phosphorylation of ERK1/2 by MEK1/2. Nemorosone also inhibits growth of Capan-1, AsPC-1, and MIA-PaCa-2 pancreatic cancer cells (IC50s = 4.5-5.0 μM following a 72-hour treatment) but not human dermal and foreskin fibroblasts (IC50s = >35 μM).1 It induces apoptosis, abolishes the mitochondrial membrane potential, and increases cytosolic calcium concentration in pancreatic cancer cells in a dose-dependent manner. Nemorosone activates the caspase cascade in a dose-dependent manner and inhibits cell cycle progression, increasing the proportion of cells in the G0/G1 phase, in both neuroblastoma and pancreatic cancer cells.1,2 Nemorosone (50 mg/kg, i.p., per day) also reduces tumor growth in an MIA-PaCa-2 mouse xenograft model.3 References1. Holtrup, F., Bauer, A., Fellenberg, K., et al. Microarray analysis of nemorosone-induced cytotoxic effects on pancreatic cancer cells reveals activation of the unfolded protein response (UPR). Br. J. Pharmacol. 162(5), 1045-1059 (2011).2. Díaz-Carballo, D., Malak, S., Bardenheuer, W., et al. Cytotoxic activity of nemorosone in neuroblastoma cells. J. Cell. Mol. Med. 12(6B), 2598-2608 (2008).3. Wold, R.J., Hilger, R.A., Hoheisel, J.D., et al. In vivo activity and pharmacokinetics of nemorosone on pancreatic cancer xenografts. PLoS One 8(9), e74555 (2013).

(±)-ErSO is the racemic form of ErSO. ErSO is a selective anticipatory activator of the unfolded protein response (a-UPR).

ErSO-DFP is an expected activator of the unfolded protein response (a-UPR). erSO-DFP improves selectivity for oestrogen receptor alpha+ (ERα+) cancer cells with higher selectivity than ErSO. erSO-DFP has anti-tumour effects and significantly eliminates MCF-7 tumours in a mouse model.

4μ8C (IRE1 Inhibitor III) is a highly selective and potent inhibitor of IRE1α ribonuclease (RNase) activity (IC₅₀ ≈ 6–10 μM). By forming a covalent bond with the RNase active site of IRE1α, 4μ8C specifically inhibits its ribonuclease activity, thereby blocking the splicing of XBP1 mRNA. 4μ8C can be used in research on endoplasmic reticulum stress, the unfolded protein response, immune regulation, and tumor and metabolic diseases.

Z36 is a novel Bcl-xL inhibitor, upregulating the expression levels of FAM134B, LC3, and Atg9, inducing autophagy along with autophagic cell death, resulting in ER stress and the unfolded protein response (UPR).