GW441756|504433-23-2|安捷凯

Background

GW441756 is an inhibitor of TrkA kinase and LRRK2 with IC50 value of 320nM and 2nM, respectively [1].

The activity of TrkA kinase can affect its downstream signaling and involves in many biological processes including proliferation, differentiation and apoptosis. Thereby the inhibitor of TrkA is developed for the treatment of cancers. GW441756 belongs to the oxindole series and is found to be a potent inhibitor of TrkA. It is also selective against TrkA. The IC50 values of it for cRaf1 and CDK2 are above 12μM and 7μM, respectively. In human muscle sarcoma cancer cell line HTB114, treatment of GW441756 dose-dependently suppresses neoplastic proliferation and induces apoptosis [1, 2].

In addition, GW441756 is also found to be an LRRK2 inhibitor. It inhibits the Ser935 phosphorylation of LRRK2 in cellular TR-FRET assay with IC50 value of 2.2μM. It shows no significant cytotoxicity with IC50 value of >20μM [3].

参考文献:
[1] Wood E R, Kuyper L, Petrov K G, et al. Discovery and in vitro evaluation of potent TrkA kinase inhibitors: oxindole and aza-oxindoles. Bioorganic & medicinal chemistry letters, 2004, 14(4): 953-957.
[2] Montagnoli C, Pistilli A, Stabile A M, et al. Anti-proliferative effects of GW441756, a novel inhibitor of NGFreceptor tyrosine kinase a (TRKA), in human sarcoma. Italian Journal of Anatomy and Embryology, 2010, 115(1/2): 117.
[3] Hermanson S B, Carlson C B, Riddle S M, et al. Screening for novel LRRK2 inhibitors using a high-throughput TR-FRET cellular assay for LRRK2 Ser935 phosphorylation. PloS one, 2012, 7(8): e43580.

Protocol

Cell experiment [1]:

Cell lines

human muscle sarcoma cancer cell line HTB114

Preparation method

The solubility of this compound in DMSO is >13.8mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

IC50 = 2nM

Applications

In human muscle sarcoma cancer cell line HTB114, GW441756 dose-dependently decreased neoplastic proliferation and significantly increased apoptosis in a dose-dependent way. GW441756 also increased the level of caspase-3, which then led to apoptosis.

Animal experiment [2]:

Animal models

Alzheimer’s disease (AD) mouse model, PDAPP (J20) mice

Dosage form

10 mg/kg/day (subcutaneous injection, Sub-Q); 5 days

Application

In Alzheimer’s disease (AD) mouse model, PDAPP (J20) mice, GW441756 at 10 mg/kg increased the level of sAβPPα and increased the sAβPPα to Aβ42 ratio to 1.85 times over control. At this dose, GW441756 gave measurable brain levels with a maximum brain concentration (Cmax, 1 h) of ~1×IC50 (50 nM).

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

参考文献:

[1]. Montagnoli C, Pistilli A, Stabile A M, et al. Anti-proliferative effects of GW441756, a novel inhibitor of NGFreceptor tyrosine kinase a (TRKA), in human sarcoma. Italian Journal of Anatomy and Embryology, 2010, 115(1/2): 117.

[2]. Zhang Q#1, Descamps O#1, Hart MJ1, et al. Paradoxical effect of TrkA inhibition in Alzheimer's disease models. J Alzheimers Dis. 2014;40(3):605-617.

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生命科学

有机化学

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材料科学

GW441756

GW441756详情

Background

Protocol

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