IRE1 Inhibitor

Sunitinib (SU 11248) is a multi-targeted receptor tyrosine kinase inhibitor with IC₅₀s of 80 nM and 2 nM for VEGFR2 and PDGFRβ, respectively. Sunitinib, an ATP-competitive inhibitor, effectively inhibits autophosphorylation of Ire1α by inhibiting autophosphorylation and consequent RNase activation.

4μ8C (IRE1 Inhibitor III) is a small-molecule inhibitor of IRE1α.

IXA4 is a highly selective, non-toxic IRE1/XBP1s activator. IXA4 activates IRE1/XBP1s signaling without globally activating the unfolded protein response (UPR) or other stress-responsive signaling pathways (e.g., the heat shock response or oxidative stress response). IXA4 reduces secretion of APP through IRE1 activation.

STF-083010 is a specific IRE1α inhibitor. STF-083010 inhibits Ire1 endonuclease activity, without affecting its kinase activity, after endoplasmic reticulum stress.

MKC8866, a salicylaldehyde analog, is a potent, selective IRE1 RNase inhibitor with an IC₅₀ of 0.29 μM in human vitro. MKC8866 strongly inhibits Dithiothreitol-induced X-box-binding protein 1-spliced (XBP1s) expression with an EC₅₀ of 0.52 μM and unstresses RPMI 8226 cells with an IC₅₀ of 0.14 μM. MKC8866 inhibits IRE1 RNase in breast cancer cells leading to the decreased production of pro-tumorigenic factors and it can inhibits prostate cancer (PCa) tumor growth.

Sunitinib (SU 11248) Malat is a multi-targeted receptor tyrosine kinase inhibitor with IC₅₀s of 80 nM and 2 nM for VEGFR2 and PDGFRβ, respectively. Sunitinib Malat, an ATP-competitive inhibitor, effectively inhibits autophosphorylation of Ire1α by inhibiting autophosphorylation and consequent RNase activation.

KIRA6 is an advanced small-molecule IRE1α RNase kinase inhibitor with an IC₅₀ of 0.6 µM. KIRA6 can trigger an apoptotic response.

Toyocamycin (Vengicide) is an adenosine analog produced by Streptomyces diastatochromogenes, acts as an XBP1 inhibitor. Toyocamycin blocks RNA synthesis and ribosome function, and induces apoptosis. Toyocamycin affects IRE1α-XBP1 pathway, and inhibits XBP1 mRNA cleavage with an IC₅₀ value of 80 nM with affecting IRE1α auto-phosphorylation. Toyocamycin specifically inhibits CDK9 with an IC₅₀ value of 79 nM.

Kira8 (AMG-18) is a mono-selective IRE1α inhibitor that allosterically attenuates IRE1α RNase activity with an IC₅₀ of 5.9 nM.

APY29, an ATP-competitive inhibitor, is an allosteric modulator of IRE1α which inhibits IRE1α autophosphorylation by binding to the ATP-binding pocket with IC₅₀ of 280 nM. APY29 acts as a ligand that allosterically activates IRE1α adjacent RNase domain.

MKC3946 is a potent IRE1α inhibitor, used for cancer research.

GSK2850163 is a novel inhibitor of inositol-requiring enzyme-1 alpha (IRE1α) which can inhibit IRE1α kinase activity and RNase activity with IC₅₀s of 20 and 200 nM, respectively.

Hexadecanedioic acid (Thapsic acid) is an orally active metabolite produced by B. uniformis. Hexadecanedioic acid inhibits IRE1α-XBP1s-mediated flipogenesis and ferroptosis. Hexadecanedioic acid downregulates XBP1 and Hrd1 expression, activates the Nrf2/SLC7A11/GPX4 pathway. Hexadecanedioic acid can be used for the research of metabolic-associated fatty liver disease.

B I09 is an IRE-1 RNase inhibitor, with an IC₅₀ of 1230 nM.

IRE1α kinase-IN-1 is a highly selective IRE1α (ERN1) inhibitor, with an IC₅₀ of 77 nM. IRE1α kinase-IN-1 displays 100-fold selectivity for IRE1α over the IRE1β isoform. IRE1α kinase-IN-1 inhibits ER stress-induced IRE1α oligomerization and autophosphorylation, and also inhibits IRE1α RNase activity (IC₅₀=80 nM).

Tauroursodeoxycholate dehydrate is an orally active taurine conjugate of Ursodeoxycholic acid (HY-13771). Tauroursodeoxycholate dehydrate inhibits caspase-3/7, Apoptosis, IRE1α/TRAF2/NF-κB, prevents JNK phosphorylation, inhibits ROS generation, and activates Akt signaling. Tauroursodeoxycholate dehydrate prevents cataract formation, reduces renal tubular damage in type 2 diabetic mice, reduces I/R injury in liver, and inhibits intestinal inflammation and barrier disruption in nonalcoholic fatty liver disease.

G-5758 is a selective and orally effective IRE1α inhibitor with an IC₅₀ of 38 nM (detected by the XBP1s luciferase reporter cell assay). G-5758 is still well tolerated in rats at oral doses up to 500 mg/kg. G-5758 can be used in the research of multiple myeloma.

IXA62 is an orally active and selective IRE1/XBP1s activator (EC₅₀ = 0.31 μM) that reduces Aβ secretion. IXA62 enhances glucose-stimulated insulin secretion from rat insulinoma cells.

3,6-DMAD hydrochloride, an acridine derivative, is a potent IRE1α-XBP1s pathway inhibitor. 3,6-DMAD hydrochloride promotes IL-6 secretion via the IRE1α-XBP1s pathway. 3,6-DMAD hydrochloride inhibits IRE1α oligomerization and endoribonuclease (RNase) activity. 3,6-DMAD hydrochloride can be used for research of cancer.

KIRA-7, an imidazopyrazine compound, binds the IRE1α kinase (IC₅₀ of 110 nM) to allosterically inhibit its RNase activity. KIRA-7 has an anti-fibrotic effect.