unfolded protein response (upr)

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

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.

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.

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.

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).

BOLD-100 free base (NKP-1339; IT-139), a ruthenium-based anticancer agent, inhibits stress-induced GRP78 upregulation, thus disrupting endoplasmic reticulum (ER) homeostasis. This action induces ER stress and unfolded protein response (UPR), interfering with the intricate relationship between ER-stress response, lysosome dynamics, and autophagy execution.

IRE1α kinase-IN-9 (compound 2) is a potent inhibitor of IRE-1α with an average IC50 value of less than 0.1 μM, and it is suitable for research into diseases related to the unfolded protein response or regulated IRE1-dependent decay (RIDD) [1].

Mono-Pt, the first platinum(II) complex to inhibit cancer cells via a non-DNA-binding mitophagy pathway, promotes mitophagy in cancer cells by inducing endoplasmic reticulum stress (ERS) and activating the unfolded protein response (UPR) [1].

SpiD3 is an antitumor spirocyclic dimer with the advantage of being independent of TME (tumor microenvironment) stimulation. It induces apoptosis in chronic lymphocytic leukemia (CLL) cells, inhibits NF-κB activation, upregulates the UPR (unfolded protein response), and suppresses protein synthesis. It can be used to study BTK-mutated CLL.

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.

Mycothiazole is an inhibitor of mitochondrial electron transport chain (ETC) complex I. It exhibits cytotoxicity in cancer cells Huh7 (IC50 of 55.8 μM), U87, and MCF7. In Huh7 cells, Mycothiazole induces apoptosis (apoptosis). Additionally, Mycothiazole extends the lifespan of C. elegans by modulating transcription factors ATFS-1 and HSF1, which are associated with the unfolded protein response (UPR) and heat shock response (HSR).