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Purity: ≥98%
STF-083010 (formerly IRE1 Inhibitor I) is a novel and specific small-molecule inhibitor of IRE1α endonuclease. In many solid tumors and hematologic malignancies, including multiple myeloma (MM), the adaptive Ire1-XBP1 pathway has been found to be activated. Following endoplasmic reticulum stress in both vitro and vivo, STF-083010 reduced Ire1 endonuclease activity without affecting its kinase activity. In models of human MM xenografts, STF-083010 treatment demonstrated significant antimyeloma activity. STF-083010, in contrast to other similarly isolated cell populations, was preferentially toxic to freshly isolated human CD138(+) MM cells. The discovery of this new Ire1 inhibitor lends credence to the idea that the Ire1-XBP1 axis represents a promising target for anticancer therapy, particularly in the context of MM. STF-083010 exhibits dose- and time-dependent cytostatic and cytotoxic activity in MM.1S, MM.1R, and RPMI 8226 MM cell lines. STF-083010 blocks IRE1α's endonuclease activity without affecting its kinase activity in the MiaPaCa2, Panc0403, and SU8686 cell lines. It also inhibits the splicing of XBP1. After three days of culture, STF-083010 shows a 70% growth inhibition in Eμ-TCL1 CLL cells. STF-083010 inhibits 20% of growth in MEC1 and MEC2 cells within 48 hours. WaC3 cells react to STF-083010 treatments by gradually slowing their growth.
Targets |
Ire1
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ln Vitro |
STF-083010 exhibits dose- and time-dependent cytotoxic and cytostatic activity in MM.1S, MM.1R, and RPMI 8226 MM cell lines.[1] [2] STF-083010 blocks IRE1's endonuclease activity in MiaPaCa2, Panc0403, and SU8686 cell lines without affecting XBP1 splicing or its kinase activity.[1] After three days of culture, STF-083010 shows a growth inhibition of about 70% in STF-083010 exhibits dose- and time-dependent cytotoxic and cytostatic activity in MM.1S, MM.1R, and RPMI 8226 MM cell lines. [1] [2] STF-083010 blocks IRE1's endonuclease activity in MiaPaCa2, Panc0403, and SU8686 cell lines without affecting XBP1 splicing or its kinase activity. [1] After three days of culture, STF-083010 shows a growth inhibition of about 70% in E-TCL1 CLL cells. In 48 hours, STF-083010 inhibits 20% of growth in MEC1 and MEC2 cells. WaC3 cells respond to STF-083010 treatments by gradually slowing their growth. [3]-TCL1 CLL cells. In 48 hours, STF-083010 inhibits 20% of growth in MEC1 and MEC2 cells. WaC3 cells respond to STF-083010 treatments by gradually slowing their growth. [3]
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ln Vivo |
STF-083010 (i.p., 30 mg/kg) significantly slows the growth of the tumor in a human multiple myeloma (MM) xenograft model. [1]
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Enzyme Assay |
The presence of 32P-γATP controls the activity of autophosphorylation. By adding radiolabeled HAC1 508-nt RNA substrate that has been in vitro synthesized using 32P-UTP, endonuclease activity is assessed. Radiolabeled HAC1 508 nt RNA, recombinant hIRE1 protein, and the appropriate buffers are all added to STF083010. Electrophoresis of polyacrylamide gels is used to measure kinase activity. 32P-γATP or 32P-UTP autoradiography is used to quantify the products of RNA scleavage.
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Cell Assay |
The following day, drug treatment was begun after 3000 cells were seeded in 96-well plates over night. The stop solution (4 mM HCl, 0.1% Nondet P40 in isopropanol), which is added to dissolve the MTT, is then added to the cells after 48 hours of incubation. MTT is added to the cells and cultured for 4 hours at 37°C. With a reference wavelength of 630 nm, a spectrophotometer reads the plates at 590 nm absorbance. Utilizing GraphPad Prism, IC50 values are computed.
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Animal Protocol |
Mice: The right and left hind footpads of each BALB/c nude mouse (male, 5 weeks old) are subcutaneously inoculated with 5×106 HCT116 p53+/+ or HCT116 p53-/- cells. After four days, DMSO or STF-083010 (40 mg/kg) is injected intraperitoneally every three days. Every five days, tumors are measured, and their volumes are calculated using the formula mm3=(length (mm))×(width (mm))2/2).
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References | |
Additional Infomation |
Activation of the adaptive Ire1-XBP1 pathway has been identified in many solid tumors and hematologic malignancies, including multiple myeloma (MM). Here, we report the identification of STF-083010, a novel small-molecule inhibitor of Ire1. STF-083010 inhibited Ire1 endonuclease activity, without affecting its kinase activity, after endoplasmic reticulum stress both in vitro and in vivo. Treatment with STF-083010 showed significant antimyeloma activity in model human MM xenografts. Similarly, STF-083010 was preferentially toxic to freshly isolated human CD138(+) MM cells compared with other similarly isolated cell populations. The identification of this novel Ire1 inhibitor supports the hypothesis that the Ire1-XBP1 axis is a promising target for anticancer therapy, especially in the context of MM.[1]
Endoplasmic reticulum stress from unfolded proteins is associated with the proliferation of pancreatic tumor cells, making the many regulatory molecules of this pathway appealing targets for therapy. The objective of our study was to assess potential therapeutic efficacy of inhibitors of unfolded protein response (UPR) in pancreatic cancers focusing on IRE1α inhibitors. IRE1α-mediated XBP-1 mRNA splicing encodes a transcription factor that enhances transcription of chaperone proteins in order to reverse UPR. Proliferation assays using a panel of 14 pancreatic cancer cell lines showed a dose- and time-dependent growth inhibition by IRE1α-specific inhibitors (STF-083010, 2-Hydroxy-1-naphthaldehyde, 3-Ethoxy-5,6-dibromosalicylaldehyde, toyocamycin). Growth inhibition was also noted using a clonogenic growth assay in soft agar, as well as a xenograft in vivo model of pancreatic cancer. Cell cycle analysis showed that these IRE1α inhibitors caused growth arrest at either the G1 or G2/M phases (SU8686, MiaPaCa2) and induced apoptosis (Panc0327, Panc0403). Western blot analysis showed cleavage of caspase 3 and PARP, and prominent induction of the apoptotic molecule BIM. In addition, synergistic effects were found between either STF-083010, 2-Hydroxy-1-naphthaldehyde, 3-Ethoxy-5,6-dibromosalicylaldehyde, or toyocamycin and either gemcitabine or bortezomib. Our data suggest that use of an IRE1α inhibitor is a novel therapeutic approach for treatment of pancreatic cancers.[2] |
Molecular Formula |
C15H11NO3S2
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Molecular Weight |
317.38
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Exact Mass |
317.02
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Elemental Analysis |
C, 56.77; H, 3.49; N, 4.41; O, 15.12; S, 20.20
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CAS # |
307543-71-1
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Related CAS # |
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PubChem CID |
135398515
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Appearance |
Light yellow to yellow solid powder
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LogP |
4.5
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tPSA |
103.35
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SMILES |
C1=CC=C2C(=C1)C=CC(=C2/C=N/S(=O)(=O)C3=CC=CS3)O
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InChi Key |
TVIVJHZHPKNDAQ-MHWRWJLKSA-N
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InChi Code |
InChI=1S/C15H11NO3S2/c17-14-8-7-11-4-1-2-5-12(11)13(14)10-16-21(18,19)15-6-3-9-20-15/h1-10,17H/b16-10+
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Chemical Name |
(NE)-N-[(2-hydroxynaphthalen-1-yl)methylidene]thiophene-2-sulfonamide
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Synonyms |
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HS Tariff Code |
2934.99.9001
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Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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Solubility (In Vitro) |
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3.25 mg/mL (10.24 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 32.5 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2% DMSO+40%PEG 300+5% Tween80 +ddH2O: 2mg/mL  (Please use freshly prepared in vivo formulations for optimal results.) |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 3.1508 mL | 15.7540 mL | 31.5080 mL | |
5 mM | 0.6302 mL | 3.1508 mL | 6.3016 mL | |
10 mM | 0.3151 mL | 1.5754 mL | 3.1508 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration: mg/mL;
Method for preparing DMSO stock solution: mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation::Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
The IRE1α inhibitor (STF-083010) suppresses the growth in vitro and in vivo of p53-deficient human cancer cells. From: Loss of p53 enhances the function of the endoplasmic reticulum through activation of the IRE1α/XBP1 pathway.Oncotarget.2015 Aug 21;6(24):19990-20001. th> |
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Anti-proliferative activities of IRE1αinhibitors. From: Selective inhibition of unfolded protein response induces apoptosis in pancreatic cancer cells.Oncotarget.2014 Jul 15;5(13):4881-94. td> |
Effect of STF or HNA on expression of UPR target genes in pancreatic cancer cells. From: Selective inhibition of unfolded protein response induces apoptosis in pancreatic cancer cells.Oncotarget.2014 Jul 15;5(13):4881-94. td> |