Synonym
KIRA6; KIRA-6; KIRA 6;
IUPAC/Chemical Name
1-(4-(8-Amino-3-tert-butylimidazo[1,5-a]pyrazin-1-yl)naphthalen-1-yl)-3-(3-(trifluoromethyl)phenyl)urea
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)
SMILES Code
O=C(NC1=CC=CC(C(F)(F)F)=C1)NC2=C3C=CC=CC3=C(C4=C5C(N)=NC=CN5C(C(C)(C)C)=N4)C=C2
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
Biological target:
KIRA6 is an advanced small-molecule IRE1α RNase kinase inhibitor with an IC50 of 0.6 µM.
In vitro activity:
KIRA6 inhibits the kinase activity of IRE1. In a direct binding assay, KIRA6 showed a Kd value of 10.8 ± 2.9 µM. Although KIRA6 also inhibited KIT at nanomolar concentrations, it did not prompt KIT degradation, and rescued KIT from GSK2606414-mediated degradation. Consistent with KIT inhibition, nanomolar concentrations of KIRA6 were sufficient to induce cell death in a KIT signaling-dependent mast cell leukemia cell line.
Reference: Cell Death Dis. 2019 Apr 1;10(4):300. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30931942/
In vivo activity:
To test in vivo efficacy of systemic KIRA6, the Ins2+/Akita (Akita) mouse, which expresses a mutant (C96Y) proinsulin unable to complete oxidative folding, thus causing chronic ER stress, β-cell apoptosis, and diabetes in infancy was chosen. The pharmacokinetic profile of KIRA6 in BALB/c mice intraperitoneally (i.p.) dosed at 10 mg/kg showed good drug plasma AUC levels (AUC 0-24h = 14.3 μM*h) with moderate clearance (22.4 mL/min/kg). Drug half-life was 3.90 hours, Cmax was 3.3 μM, and plasma levels at 4 and 8hr were 1.2 μM and 0.33 μM, respectively. Initial systemic studies utilized a Tm i.p. challenge in C57BL/6 mice, with and without KIRA6 co-injection, and UPR markers measured in liver. Low dose Tm (2 μg/kg) elevates liver XBP1 splicing without decay of ER-localized Blos1 mRNA, while KIRA6 co-provision reduces XBP1 splicing (Figure S7A,B). Escalation of Tm to 100 μg/kg further increases XBP1 splicing and triggers Blos1 mRNA decay, with both markers attenuated by KIRA6 (Figure S7C,D).
Reference: Cell. 2014 Jul 31;158(3):534-48. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25018104/
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
6.3 |
12.05 |
| Ethanol |
2.0 |
3.86 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
518.54
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
In vitro protocol:
1. Mahameed M, Wilhelm T, Darawshi O, Obiedat A, Tommy WS, Chintha C, Schubert T, Samali A, Chevet E, Eriksson LA, Huber M, Tirosh B. The unfolded protein response modulators GSK2606414 and KIRA6 are potent KIT inhibitors. Cell Death Dis. 2019 Apr 1;10(4):300. doi: 10.1038/s41419-019-1523-3. PMID: 30931942; PMCID: PMC6443726.
In vivo protocol:
1. Ghosh R, Wang L, Wang ES, Perera BG, Igbaria A, Morita S, Prado K, Thamsen M, Caswell D, Macias H, Weiberth KF, Gliedt MJ, Alavi MV, Hari SB, Mitra AK, Bhhatarai B, Schürer SC, Snapp EL, Gould DB, German MS, Backes BJ, Maly DJ, Oakes SA, Papa FR. Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress. Cell. 2014 Jul 31;158(3):534-48. doi: 10.1016/j.cell.2014.07.002. Epub 2014 Jul 10. PMID: 25018104; PMCID: PMC4244221.
1: Liu J, Zhou S, Qian X, Zhang Y, Zhao J. [Over-expressed Bax inhibitor 1 (BI-1) inhibits apoptosis of hippocampal neurons via endoplasmic reticulum IRE1-JNK pathway in rats with subarachnoid hemorrhage]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2017 Oct;33(10):1316-1322. Chinese. PubMed PMID: 29169414.
2: Ghosh R, Wang L, Wang ES, Perera BG, Igbaria A, Morita S, Prado K, Thamsen M, Caswell D, Macias H, Weiberth KF, Gliedt MJ, Alavi MV, Hari SB, Mitra AK, Bhhatarai B, Schürer SC, Snapp EL, Gould DB, German MS, Backes BJ, Maly DJ, Oakes SA, Papa FR. Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress. Cell. 2014 Jul 31;158(3):534-48. doi: 10.1016/j.cell.2014.07.002. Epub 2014 Jul 10. PubMed PMID: 25018104; PubMed Central PMCID: PMC4244221.
