GW441756
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].
References:
[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.
| Storage | Store at -20°C |
| M.Wt | 275.3 |
| Cas No. | 504433-23-2 |
| Formula | C17H13N3O |
| Solubility | insoluble in H2O; insoluble in EtOH; ≥13.75 mg/mL in DMSO |
| Chemical Name | (3Z)-3-[(1-methylindol-3-yl)methylidene]-1H-pyrrolo[3,2-b]pyridin-2-one |
| SDF | Download SDF |
| Canonical SMILES | CN1C=C(C2=CC=CC=C21)C=C3C4=C(C=CC=N4)NC3=O |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment [1]: | |
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Cell lines |
human muscle sarcoma cancer cell line HTB114 |
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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. |
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Reacting condition |
IC50 = 2nM |
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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]: | |
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Animal models |
Alzheimer’s disease (AD) mouse model, PDAPP (J20) mice |
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Dosage form |
10 mg/kg/day (subcutaneous injection, Sub-Q); 5 days |
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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). |
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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. |
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References: [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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| Description | GW441756 is a potent, selective inhibitor of TrkA with an IC50 value of 2 nM. | |||||
| Targets | TrkA | CDK2 | C-Raf-1 | |||
| IC50 | 2 nM | >7 μM | >12 μM | |||
Quality Control & MSDS
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