KIRA6 (KIRA-6) is a novel, potent, allosteric IRE1 inhibitor with anti-inflammatory and immune-modulating properties (IC50 of 0.6 µM). KIRA6 was created to block IRE1α-mediated cell death and has since been shown to support cell survival and stop ER stress-induced cell aging in vivo.
Physicochemical Properties
| Molecular Formula | C28H25F3N6O |
| Molecular Weight | 518.5329 |
| Exact Mass | 518.204 |
| Elemental Analysis | C, 64.86; H, 4.86; F, 10.99; N, 16.21; O, 3.09 |
| CAS # | 1589527-65-0 |
| Related CAS # | 1589527-65-0 |
| PubChem CID | 73425700 |
| Appearance | Solid powder |
| Density | 1.4±0.1 g/cm3 |
| Index of Refraction | 1.645 |
| LogP | 6.26 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 38 |
| Complexity | 834 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | FC(C1C=CC=C(C=1)NC(NC1=CC=C(C2=CC=CC=C21)C1=C2C(N)=NC=CN2C(C(C)(C)C)=N1)=O)(F)F |
| InChi Key | NOHQEAFAESMMDX-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C28H25F3N6O/c1-27(2,3)25-36-22(23-24(32)33-13-14-37(23)25)20-11-12-21(19-10-5-4-9-18(19)20)35-26(38)34-17-8-6-7-16(15-17)28(29,30)31/h4-15H,1-3H3,(H2,32,33)(H2,34,35,38) |
| Chemical Name | 1-[4-(8-amino-3-tert-butylimidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl]-3-[3-(trifluoromethyl)phenyl]urea |
| Synonyms | KIRA6; KIRA 6; KIRA-6 |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| Targets | IRE1α (IC50 = 0.6 µM) |
| ln Vitro | KIRA6 inhibits Tg's autophosphorylation of IRE1α and Tm's splicing of XBP1 mRNA in INS-1 cells in a dose-dependent manner[1]. |
| ln Vivo | KIRA6 protects the functional viability of photoreceptors intravitreally in rat models of ER stress-induced retinal degeneration. Systematically, KIRA6 protects pancreatic β-cells in Akita diabetic mice, boosts insulin, and lowers hyperglycemia. In vivo, KIRA6 inhibits IRE1α to maintain cell viability and function in a variety of cells and rodent tissues under ER stress. When administered intraperitoneally (i.p.) to BALB/c mice at a dose of 10 mg/kg, KIRA6 has a good plasma AUC (AUC 0-24h = 14.3 μM*h) and a moderate clearance (22.4 mL/min/kg). The drug has a 3.90-hour half-life, a Cmax of 3.3 μM, and plasma levels at 4 and 8 hours of 1.2 μM and 0.33 μM, respectively[1]. |
| Cell Assay | Drugs were administered to cells at different concentrations. |
| Animal Protocol |
BALB/c mice 10 mg/kg i.p. |
| References |
[1]. The unfolded protein response modulators GSK2606414 and KIRA6 are potent KIT inhibitors. Cell Death Dis. 2019 Apr 1;10(4):300. [2]. Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress. Cell. 2014 Jul 31;158(3):534-48. |
Solubility Data
| Solubility (In Vitro) |
DMSO: 25~60 mg/mL (48.2~115.7 mM) Ethanol: ~60 mg/mL (~115.7 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.5 mg/mL (0.96 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 5.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL 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: ≥ 0.5 mg/mL (0.96 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 5.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 0.5 mg/mL (0.96 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 5.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9285 mL | 9.6426 mL | 19.2853 mL | |
| 5 mM | 0.3857 mL | 1.9285 mL | 3.8571 mL | |
| 10 mM | 0.1929 mL | 0.9643 mL | 1.9285 mL |