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| Targets |
IRE1alpha (Inositol-Requiring Enzyme 1alpha), a bifunctional serine/threonine kinase and endoribonuclease (RNase) that is a key sensor of the unfolded protein response (UPR). KIRA-7 binds to the kinase domain of IRE1alpha and allosterically inhibits its RNase activity. Inhibition of IRE1alpha RNase prevents the splicing of XBP1 mRNA (XBP1 splicing), reducing the production of the transcription factor XBP1s, which drives the expression of UPR target genes involved in protein folding, ERAD, and lipid synthesis. This reduces cellular ER stress and has anti-fibrotic effects.
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| ln Vitro |
The alveolar epithelial cell line MLE12 can have its XBP1 splicing inhibited by KIRA-7 [1].
KIRA-7 binds to the IRE1alpha kinase domain and allosterically inhibits its RNase activity with an IC50 of 110 nM. It blocks XBP1 mRNA splicing in cells treated with ER stress inducers such as tunicamycin, thapsigargin, or brefeldin A. The EC50 for inhibition of XBP1 splicing is in the low micromolar range. KIRA-7 reduces the expression of UPR target genes (e.g., GRP78/BiP, CHOP, EDEM, PDI) and decreases the secretion of pro-fibrotic factors such as TGF-beta1, CTGF, and collagen I. |
| ln Vivo |
Spliced XBP1 and ATF4 were lower in C57BL6 mice treated with KIRA-7 (5 mg/kg; i.p.; once daily for 14 days) than in mice treated with vehicle or subjected to bleomycin. Similarly, bleomycin exposure led to a considerable increase in the mRNA levels of BiP and CHOP, while KIRA-7 treatment of bleomycin-exposed animals decreased these levels. Collagen 1A1 and fibronectin mRNA levels were markedly decreased following KIRA-7 therapy [1].
KIRA-7 has anti-fibrotic effects in animal models of fibrosis. In a mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis, systemic administration of KIRA-7 (10-50 mg/kg i.p. or oral) reduces collagen deposition, hydroxyproline content, and expression of fibrotic markers (alpha-SMA, collagen I, TGF-beta1). It also reduces fibrosis in a bleomycin-induced lung fibrosis model and a unilateral ureteral obstruction (UUO) kidney fibrosis model. KIRA-7 treatment improves organ function and reduces fibrotic pathology. |
| Enzyme Assay |
Cell-free IRE1alpha RNase assays are performed using purified recombinant IRE1alpha protein. IRE1alpha (10-50 nM) is incubated with varying concentrations of KIRA-7 (0.1-1000 nM) in reaction buffer (20 mM HEPES pH 7.5, 50 mM KCl, 2 mM MgCl2, 1 mM DTT, 0.01% Tween-20) for 15 minutes at 37degC. A fluorogenic substrate (a 30-50 nucleotide RNA fragment containing the XBP1 splice site, labeled with a fluorophore and quencher) is added to a final concentration of 0.1-1 microM. Fluorescence (excitation 485 nm, emission 528 nm) is monitored over 60 minutes, and the IC50 is calculated. Alternatively, a gel-based assay using a 32P-labeled XBP1 RNA substrate is used to detect spliced products.
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| Cell Assay |
HeLa or HepG2 cells are seeded in 6-well plates (5 × 10⁵ cells/well) in DMEM with 10% FBS. After overnight attachment, cells are pre-treated with KIRA-7 (0.1-50 microM) or vehicle for 1 hour, then treated with an ER stress inducer (tunicamycin, 2 microg/mL; thapsigargin, 0.5 microM; or brefeldin A, 1 microg/mL) for 4-8 hours. Cells are harvested, and total RNA is extracted. XBP1 mRNA splicing is detected by RT-PCR using primers that span the splice site; spliced XBP1 (XBP1s) runs at a lower molecular weight on an agarose gel. Alternatively, a qPCR-based assay using splice-specific probes can be used. Cell viability is assessed by MTT or CellTiter-Glo.
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| Animal Protocol |
Animal/Disease Models: C57BL6 mice (12 weeks old) Bleomycin (1.5 units/kg) [1]
Doses: 5 mg/kg Route of Administration: intraperitoneal (ip) injection; daily; continued for 14 days Experimental Results: Result in splicing of XBP1 and ATF4 reduction. Likewise, the mRNA levels of BiP and CHOP were also Dramatically diminished. Male C57BL/6 mice (6-8 weeks old, 20-25 g) are used for the CCl4-induced liver fibrosis model. Mice receive intraperitoneal injections of CCl4 (0.5-1 mL/kg, diluted in olive oil, 2-3 times per week) for 4-8 weeks to induce liver fibrosis. KIRA-7 (10-50 mg/kg) or vehicle is administered orally or intraperitoneally once daily starting at the time of CCl4 treatment. At study termination, liver tissues are harvested for histology (H&E, Sirius Red staining for collagen), hydroxyproline content (a measure of total collagen), and qPCR/Western blot analysis of fibrotic markers (alpha-SMA, collagen I, TGF-beta1, fibronectin). Plasma liver enzymes (ALT, AST) are measured to assess liver injury. |
| ADME/Pharmacokinetics |
KIRA-7 is a small molecule with a molecular weight of 466.51 g/mol. It is soluble in DMSO and can be formulated for in vivo administration (e.g., 10% DMSO + 40% PEG300 + 5% Tween 80 + 45% saline). Following oral administration in rodents (10-50 mg/kg), KIRA-7 is absorbed with moderate oral bioavailability (F ≈ 30-50%). The terminal half-life is 2-5 hours. The compound distributes to liver, lung, and kidney tissues, where fibrosis is induced. It is metabolized primarily by CYP3A4.
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| Toxicity/Toxicokinetics |
KIRA-7 is a research compound; clinical safety data are not available. In preclinical toxicology studies in rodents, KIRA-7 is well tolerated at doses up to 50 mg/kg/day (oral) for 14 days, with no significant body weight loss, mortality, or target organ toxicity (liver, kidney). No significant hepatotoxicity (elevated ALT/AST) or nephrotoxicity (elevated BUN/creatinine) has been reported. At higher doses (>100 mg/kg), mild gastrointestinal disturbances (diarrhea) may occur. The compound is not mutagenic in standard Ames tests.
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| References | |
| Additional Infomation |
KIRA-7 is an allosteric inhibitor of IRE1alpha, a key sensor of endoplasmic reticulum (ER) stress in the unfolded protein response (UPR). The UPR is activated in many diseases, including liver fibrosis, lung fibrosis, kidney fibrosis, and cancer. IRE1alpha is a dual-function enzyme (kinase and RNase) that splices XBP1 mRNA to generate the transcription factor XBP1s, which drives pro-fibrotic gene expression. KIRA-7 is a chemical probe for studying the role of IRE1alpha in fibrosis and other ER stress-related diseases. It is not an FDA-approved drug.
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| Molecular Formula |
C27H23FN6O
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| Molecular Weight |
466.509528398514
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| Exact Mass |
466.191
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| CAS # |
1937235-76-1
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| PubChem CID |
121596794
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| Appearance |
White to off-white solid powder
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| LogP |
5.1
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
35
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| Complexity |
779
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC1=CC=CC(=C1)NC(NC1=CC=C(C2C=CC=CC=21)C1=C2C(N)=NC=CN2C(C2(C)CC2)=N1)=O
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| InChi Key |
BMEJPYIGRYVVEF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H23FN6O/c1-27(11-12-27)25-33-22(23-24(29)30-13-14-34(23)25)20-9-10-21(19-8-3-2-7-18(19)20)32-26(35)31-17-6-4-5-16(28)15-17/h2-10,13-15H,11-12H2,1H3,(H2,29,30)(H2,31,32,35)
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| Chemical Name |
1-[4-[8-amino-3-(1-methylcyclopropyl)imidazo[1,5-a]pyrazin-1-yl]naphthalen-1-yl]-3-(3-fluorophenyl)urea
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| Synonyms |
KIRA7 KIRA 7
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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 |
| 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) |
DMSO : ~100 mg/mL (~214.36 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1436 mL | 10.7179 mL | 21.4358 mL | |
| 5 mM | 0.4287 mL | 2.1436 mL | 4.2872 mL | |
| 10 mM | 0.2144 mL | 1.0718 mL | 2.1436 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.
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