KIRA6 is highlighted as a sophisticated small-molecule inhibitor targeting the IRE1α RNase kinase, displaying an IC50 of 0.6 µM[2].
体内研究
Administered via intraperitoneal injection at 5 mg/kg for 37 days, KIRA6 notably improves random glucose levels over time when compared to a vehicle, under a free-feeding regimen[2].
Also, following 21 or 18 days post-injections, it elevates plasma insulin and C-peptide levels and sustains high levels of insulin-positive islet areas in the Akita Mouse, demonstrating its efficacy in glucose management and insulin secretion enhancement[2].
体外研究
It has an affinity for the cytoplasmic domain of KIT, with a Kd value of 10.8 μM, covering a concentration range from 1nM to 100μM[1].
At concentrations of 10-1000 nM over a period of 72 hours, KIRA6 significantly diminishes the viability of the KIT-dependent HMC-1.1 cell line, an effect that is consistent with its ability to block KIT[1].
Within just an hour of treatment at the same concentration range, KIRA6 lowers the signaling output of KIT, including the phosphorylation of KIT itself and its downstream effectors, PSTAT5, and phosphorylated ERK1/2[1].
Furthermore, KIRA6 at 1 μM inhibits the decay of Ins1 mRNA resulting from IRE1α overactivation in a dose-responsive manner over 48 hours[2].
Additionally, between 0.1 to 10μM for 72 hours, it systematically decreases the enhancement of Ins1 apoptosis triggered by 1NM-PP1 under ER stress conditions in a dose-dependent way[2].
KIRA6 细胞实验
Cell Line
Concentration
Treated Time
Description
References
MEL526 cells
100 nM - 1 µM
1 hour
KIRA6 inhibited KIT phosphorylation at concentrations similar to that of GSK414.
Cell Death Dis. 2019 Apr 1;10(4):300.
3T3-L1 preadipocytes
1 µM
24 hours
To evaluate the inhibitory effect of KT-NE on adipocyte differentiation and lipid droplet accumulation, results showed that KT-NE significantly inhibited adipocyte differentiation and lipid droplet accumulation
Nat Commun. 2024 Jan 2;15(1):72.
HUVECs
1 µM
24 hours
To assess the toxicity of KT-NE on normal somatic cells, results showed that KT-NE had negligible toxicity on HUVEC cells within 24 hours
Nat Commun. 2024 Jan 2;15(1):72.
HMC-1.1 cells
10 nM - 1 µM
72 hours
KIRA6 compromised the viability of KIT-dependent HMC-1.1 cells.
Cell Death Dis. 2019 Apr 1;10(4):300.
HEY cells
2 µM
72 hours
Kira6 reversed the apoptosis and activation of IRE1α/JNK pathway induced by ROR2 overexpression
J Transl Med. 2019 Dec 26;17(1):428.
HO-8910 cells
2 µM
72 hours
Kira6 reversed the apoptosis and activation of IRE1α/JNK pathway induced by ROR2 overexpression
J Transl Med. 2019 Dec 26;17(1):428.
Primary human airway epithelial (HAE) cells
100 nM
72 hours
KIRA6 inhibits IL-1β-induced XBP1 splicing and MUC5AC and MUC5B mRNA expression
Am J Respir Crit Care Med. 2019 Jul 15;200(2):220-234.
KIRA6 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
Traumatic brain injury (TBI) model
Intraperitoneal injection
10 mg/kg
Once daily for three consecutive days
Kira6 alleviated neuroinflammation and neuronal death caused by PAD4 overexpression by inhibiting the IRE1α/ASK1/JNK signaling pathway.
J Neuroinflammation. 2023 Sep 30;20(1):222
C57BL/6 mice
High-fat diet-induced obesity model
Subcutaneous injection
4 mg/kg
Twice per week for 3 weeks
To evaluate the anti-obesity effect of KT-NE in vivo, results showed that KT-NE significantly reduced body weight and fat content in mice and improved hepatic steatosis
Nat Commun. 2024 Jan 2;15(1):72.
Kunming mice
Intracerebral hemorrhage model
Intranasal administration
5 mg/kg, 10 mg/kg, 20 mg/kg
Single administration
KIRA6 dose-dependently inhibited p-IRE1α/IRE1α protein expression, increased hematoma volume and neurological deficits.
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