GSK2606414 (Synonyms: GSK 2606414;GSK-2606414) |
| Catalog No.GC17450 |
GSK2606414 es un inhibidor selectivo de la quinasa similar a la proteína R del retículo endoplásmico (PERK) de administración oral, con un valor de IC50 de 0.4 nM.
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Cas No.: 1337531-36-8
Sample solution is provided at 25 µL, 10mM.
GSK2606414 es un inhibidor selectivo de la quinasa similar a la proteína R del retículo endoplásmico (PERK) de administración oral, con un valor de IC50 de 0.4 nM[1]. GSK2606414 es un inhibidor potente de KIT (Kd=664±294 nM), una quinasa de receptor tipo III (RTK)[2]. GSK2606414 también inhibe RIPK1, una quinasa involucrada en la muerte celular mediada por TNFα[3]. Además, GSK2606414 presenta actividad anticancerígena y es un posible inhibidor de la proteína ABCG2, también conocida como proteína de resistencia al cáncer de mama (BCRP)[4].
In vitro, el tratamiento con GSK2606414 (0.01-50µM) de la línea celular de epitelio pigmentario de la retina humana (células ARPE-19) durante 24-72h inhibió la viabilidad celular de manera dependiente de la dosis y el tiempo, pero no indujo apoptosis, inhibió la fosforilación de eIF2α inducida por thapsigargina (TG) y redujo los niveles de expresión de la proteína homóloga de unión a CHOP y del factor de crecimiento endotelial vascular (VEGF)[5]. El tratamiento con GSK2606414 (0.5 y 1µM) de células Neuro2a durante 24h redujo significativamente la producción de ROS inducida por glucosa alta (HG), atenuó la disfunción mitocondrial y la apoptosis neuronal inducida por HG, y disminuyó la expresión de la proteína GRP78 en el retículo endoplásmico[6].
In vivo, la administración oral de GSK2606414 (100mg/kg/día) a ratones modelo de enfermedad de Parkinson (EP) durante 21 días protegió a las neuronas dopaminérgicas de la sustancia negra de los neurotoxinas, aumentó la tasa de supervivencia de las neuronas dopaminérgicas en la parte compacta de la sustancia negra (SNpc) y mejoró el rendimiento motor de los ratones con EP, aunque indujo toxicidad pancreática[7].
References:
[1] Axten J M, Medina J R, Feng Y, et al. Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl) phenyl] acetyl}-2, 3-dihydro-1 H-indol-5-yl)-7 H-pyrrolo [2, 3-d] pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)[J]. Journal of medicinal chemistry, 2012, 55(16): 7193-7207.
[2] Mahameed M, Wilhelm T, Darawshi O, et al. The unfolded protein response modulators GSK2606414 and KIRA6 are potent KIT inhibitors[J]. Cell death & disease, 2019, 10(4): 300.
[3] Ouyang Y. The Involvement of Receptor Interacting Protein Kinase 1 (RIPK1) in the Pathogenesis of Acute Pancreatitis[M]. The University of Liverpool (United Kingdom), 2017.
[4] Yu Z Z, Xu B Q, Wang Y Y, et al. GSK2606414 sensitizes ABCG2-overexpressing multidrug-resistant colorectal cancer cells to chemotherapeutic drugs[J]. Biomedicines, 2023, 11(11): 3103.
[5] Jiang X, Wei Y, Zhang T, et al. Effects of GSK2606414 on cell proliferation and endoplasmic reticulum stress associated gene expression in retinal pigment epithelial cells[J]. Molecular Medicine Reports, 2017, 15(5): 3105-3110.
[6] Gundu C, Arruri V K, Sherkhane B, et al. GSK2606414 attenuates PERK/p-eIF2α/ATF4/CHOP axis and augments mitochondrial function to mitigate high glucose induced neurotoxicity in N2A cells[J]. Current research in pharmacology and drug discovery, 2022, 3: 100087.
[7] Mercado G, Castillo V, Soto P, et al. Targeting PERK signaling with the small molecule GSK2606414 prevents neurodegeneration in a model of Parkinson's disease[J]. Neurobiology of disease, 2018, 112: 136-148.
| Experimentos celulares [1]: | |
Líneas celulares | Células ARPE-19 |
Método de preparación | Las células ARPE-19 se sembraron en una placa de 96 pocillos a una densidad de 2×10³ células/pocillo y se incubaron con 0.01-50µM de GSK2606414 durante 24, 48 o 72 horas a 37°C. |
Condiciones de reacción | 0.01-50µM; 24, 48 o 72 horas |
Áreas de aplicación | GSK2606414 inhibe la viabilidad celular de manera dependiente de la dosis y el tiempo. |
| Experimentos con animales [2]: | |
Modelos animales | Ratones machos C57BL/6 de tipo salvaje |
Método de preparación | Los ratones fueron inyectados con 6-OHDA y tratados con GSK2606414 (100 mg/kg/día) por vía oral durante 21 días. Posteriormente, fueron sacrificados y se extrajeron rápidamente los cerebros, diseccionando el estriado. |
Forma de dosificación | 100 mg/kg/día; administración oral (p.o.) |
Áreas de aplicación | GSK2606414 protegió a las neuronas dopaminérgicas nigroestriatales contra una neurotoxina inductora de la enfermedad de Parkinson, mejorando el rendimiento motor. |
Referencias: [1] Jiang X, Wei Y, Zhang T, et al. Efectos de GSK2606414 sobre la proliferación celular y la expresión de genes asociados al estrés del retículo endoplásmico en células de epitelio pigmentario de la retina[J]. Molecular Medicine Reports, 2017, 15(5): 3105-3110. [2] Mercado G, Castillo V, Soto P, et al. La inhibición de la señalización PERK con la pequeña molécula GSK2606414 previene la neurodegeneración en un modelo de la enfermedad de Parkinson[J]. Neurobiology of disease, 2018, 112: 136-148. | |
| Cas No. | 1337531-36-8 | SDF | |
| Sinónimos | GSK 2606414;GSK-2606414 | ||
| Chemical Name | 1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-[3-(trifluoromethyl)phenyl]ethanone | ||
| Canonical SMILES | CN1C=C(C2=C1N=CN=C2N)C3=CC4=C(C=C3)N(CC4)C(=O)CC5=CC(=CC=C5)C(F)(F)F | ||
| Formula | C24H20F3N5O | M.Wt | 451.44 |
| Solubility | ≥ 22.57 mg/mL in DMSO, ≥ 12.03 mg/mL in EtOH with ultrasonic and warming | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
||
| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2151 mL | 11.0757 mL | 22.1513 mL |
| 5 mM | 0.443 mL | 2.2151 mL | 4.4303 mL |
| 10 mM | 0.2215 mL | 1.1076 mL | 2.2151 mL |
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- Purity: >99.50%
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Related Biological Data
RGNNV infection produced SGs through the PERK pathway.(D) The cells were treated with DMSO, 2-AP, GSK, or PBS for 1 h, and the medium was changed, and the cells were inoculated with RGNNV for 4 h, and the medium containing DMSO, 2-AP, GSK, or PBS was changed again.
GSK2606414 were purchased from GlpBio (United States) and were dissolved in DMSO.
Front Immunol 13 (2022). PMID: 35935992 IF: 8.7864 -
Related Biological Data
ER stress inhibitor (GSK) and ferroptosis inhibitor (Fer-1) attenuate lipid accumulation, iron overload, and lipid peroxidation in HepG2 cells treated with OA ＋ LPS. (A)-(D).TG, MDA, iron, and GSH levels in cells treated with inhibitors.
Fer-1 (1 μM) and GSK (GlpBio) (10 μM) treatment significantly decreased intracellular TG, MDA, and iron levels compared with OA ＋ LPS group and reversed the reduction of intracellular GSH.
Biochem Bioph Res Co 640 (2023): 183-191. PMID: 36516527 IF: 3.322
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