c-Jun N-terminal kinases (JNK) are a family of mitogen-activated protein kinases that can be activated in response to inflammatory cytokines, ischemia, UV irradiation, and heat shock. AS-601245 is a benzothiazole acetonitrile derivative that inhibits three human JNK isoforms JNK1, JNK2, and JNK3 with IC50 values of 150, 220, and 70 nM, respectively. It also exhibited 10- to 20-fold selectivity over c-Raf, CDK2, and c-src and > 50- to 100-fold selectivity over Ser/Thr- and Tyr-protein kinases. The oral administration of C3H/HEN mice with AS-601245 at 0.3, 1, 3, and 10 mg/kg decreased LPS-induced TNF-α release in a dose-dependent manner. The i.p. injection of AS601245 (40, 60, and 80 mg/kg) 1 h before and 24 h after the reperfusion dose-dependently decreased hippocampal damage in mice (16, 74, and 83%, respectively). When mice were injected with AS-601245 15 min and 24 h after the reperfusion at the above-mentioned doses, the hippocampal damage was decreased by 29, 40, and 52%, respectively. The i.p. administration of AS-601245 at 60 mg/kg led to a significant reduction in the number of phospho-c-Jun-stained neurons. AS-601245 at the doses of 18 and 60 mg/kg significantly reduced the size of cortical lesions in mice following middle cerebral artery occlusion by 27 and 52%, respectively[2].
作用机制
AS-601245 is a structurally unique JNK inhibitor. It inhibits isolated human JNK3 in an ATP-competitive manner[2].
AS601245 细胞实验
Cell Line
Concentration
Treated Time
Description
References
mouse placental trophoblasts
1 µM
1 h
inhibited FST-induced migration and invasion of trophoblasts
Cells. 2022 Nov 29;11(23):3816
KGN cells
12.5, 25, 50, 100 μM
30 min
Inhibition of JNK pathway resulted in a dose-dependent reduction in the expression of phospho-c-JunSer63.
Cell Death Dis. 2018 Apr 1;9(4):421
human teratocarcinoma cells (differentiated to neurons)
3–10 μM
inhibited NGF and serum deprivation-induced neuronal cell death by 30–40%
Br J Pharmacol. 2004 Jul;142(6):953-60
AS601245 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mouse
LPS-sensitized hypoxic-ischemic brain injury model
Intraperitoneal injection
20 or 40 mg/kg
Administered at 30 minutes before and immediately after LPS + HI
AS601245 at a dose of 20 mg/kg was more effective than 40 mg/kg in attenuating LPS-sensitized HI brain injury, including reducing cortical injury, increasing myelination, and decreasing astrogliosis
J Neuroinflammation. 2014 Dec 24;11:215
Wistar rats
Neonatal pneumococcal meningitis model
Intracerebroventricular injection
200 nmol
Single dose 4 hours before infection
Evaluate the effect of JNK inhibition on hippocampal apoptosis; results showed AS601245 significantly inhibited c-Jun phosphorylation but did not affect hippocampal apoptosis
Neurobiol Dis. 2008 Oct;32(1):142-50
Rat pups
LPS-sensitized hypoxic-ischemic brain injury model
Intraperitoneal injection
20 or 40 mg/kg
30 minutes before and immediately after LPS + HI
AS601245 significantly reduced neuroinflammation, BBB damage, and cell apoptosis, and protected against white matter injury in the immature brain.
J Neuroinflammation. 2012 Jul 17;9:175
SCID mice
Human GCT xenograft model
Intraperitoneal injection
10 mg/kg
Single injection, observed for 28 days
Inhibition of JNK pathway significantly halted in vivo growth of GCT and significantly decreased serum AMH levels.
Cell Death Dis. 2018 Apr 1;9(4):421
Mongolian gerbils
Global cerebral ischaemia model
Intraperitoneal injection
80 mg/kg
15 minutes and 24 hours after restoration of carotid blood flow
AS601245 reduced damage to neurites by 67% (P<0.001 vs controls) and activation of astrocytes by 84% (P<0.001 vs controls), and prevented ischaemia-induced impairment of memory.
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