A pan-Trk, ROS1, and ALK inhibitor
The receptor tyrosine kinases (RTKs) play a critical role, controlling cell proliferation, survival, and differentiation of normal cells. The anaplastic lymphoma kinase (ALK), a transmembrane RTK, originally identified in the nucleophosmin (NPM)–ALK chimera of anaplastic large cell lymphoma, has emerged as a novel tumorigenic player in several human cancers. Entrectinib is an orally available small-molecule inhibitor of ALK kinase activity.
In vitro: Entrectinib potently and selectively inhibits the in vitro growth of ALK-driven tumors, with confirmed mechanism of action [1].
In vivo: Since Entrectinib is able to pass the blood-brain barrier, the compound was also tested for efficacy in an xenograft model with ALK positive NSCLC tumors. MRI imaging demonstrated that Entrectinib was able to effectively and control the growth of these intracranial tumors dose-dependently, leading to increased survival [1].
Clinical trial: Entrectinib is an orally available small-molecule inhibitor of ALK kinase activity that is being evaluated in phase I/II clinical study to treat solid cancer
Reference:
[1] Elena Ardini, Maria Menichincheri, Patrizia Banfi, Daniele Casero, M.?Laura Giorgini, M. Beatrice Saccardo, Nadia Amboldi, Nilla Avanzi, Paolo Orsini, Antonella Isacchi, Enrico Pesenti, Arturo Galvani. The ALK inhibitor NMS-E628 also potently inhibits ROS1 and induces tumor regression in ROS-driven models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2092. doi:10.1158/1538-7445.AM2013-2092
| Cell experiment [1]: | |
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Cell lines |
SH-SY5Y cells stably transfected with TrkB |
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Preparation method |
The solubility of this compound in DMSO is > 28.1 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months. |
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Reacting condition |
1 ~ 200 nM; 1 hr |
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Applications |
In SY5Y-TrkB cells, Entrectinib inhibited Trk phosphorylation in a dose-dependent manner. At the dose as low as 1 nM, Entrectinib significantly inhibited Trk phosphorylation, and complete inhibition was achieved at the concentration of 10 nM or higher concentrations. Meanwhile, Entrectinib showed no effect on the Trk-null parental SH-SY5Y cells. |
| Animal experiment [1]: | |
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Animal models |
Nu/nu mice bearing SY5Y-TrkB cells |
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Dosage form |
60 mg/kg; p.o.; b.i.d., 7 days/week |
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Applications |
Entrectinib significantly inhibited tumor growth and prolonged EFS. Analyses of the tumors collected at different time points after treatment (1, 4 and 6 hrs, respectively) indicated inhibition of TrkB phosphorylation in mice treated with Entrectinib. Moreover, phosphorylation of p-PLCγ, p-Akt and p-Erk was also inhibited in Entrectinib-treated mice. In addition, Western blot results also indicated that phosphoprotein expression was significantly suppressed in xenografts upon Entrectinib treatment. |
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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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参考文献: [1]. Iyer R, Wehrmann L, Golden RL, Naraparaju K, Croucher JL, MacFarland SP, Guan P, Kolla V, Wei G, Cam N, Li G, Hornby Z, Brodeur GM. Entrectinib is a potent inhibitor of Trk-driven neuroblastomas in a xenograft mouse model. Cancer Lett. 2016 Mar 28;372(2):179-86. | |
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