Background
FRAX597 is a small-molecule inhibitor of the group 1 p21-activated kinases (PAKs) with IC50 values of 8nM, 13nM and 19nM, respectively for PAK1, PAK2 and PAK3 [1].
The PAKs family includes two sub groups: 1 and 2. These kinases take participate in the growth of various types of cancers. FRAX597 is developed to be an inhibitor of group 1 PAKs from the initial hits of a high throughput screen. It is an ATP-competitive inhibitor of PAK 1-3. To group 2 PAKs, FRAX597 shows minimal inhibitory activity. The inhibition mechanism of FRAX597 is that it binds PAK by targeting the ATP binding site and competes with ATP. FRAX597 is reported to suppress cell proliferation by arresting cell cycle in G1 without impacting cell viability in Schwann cells. In vivo assay also demonstrates FRAX597 can suppress tumor growth in an orthotopic model of NF2. This effect on the cells has been proved to be mediated through the inhibition of the group I PAKs [1].
参考文献:
[1] Silvia Licciulli, Jasna Maksimoska, Chun Zhou, Scott Troutman, Smitha Kota, Qin Liu, Sergio Duron, David Campbell, Jonathan Chernoff, Jeffery Field, Ronen Marmorstein and Joseph L. Kissil. FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits schwannomas tumorigenesis of NF2-associated. J. Biol. Chem. 2013, August.
Protocol
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Cell experiment [1]:
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Cell lines
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Nf2-null SC4 Schwann cells
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Preparation method
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Limited solubility. 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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Reaction Conditions
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96 h
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Applications
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FRAX597 treatment significantly inhibits cellular proliferation. FRAX597-treated cells are increased in G1phase (74% versus 50% in control-treated cells) and decreased in the fraction of cells in S phase (12% versus 27% in control) and G2/M phase (11% versus 22% in control).
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Animal experiment [1]:
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Animal models
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NOD/SCID mice (8 weeks of age), transplanted with Nf2-/- SC4 Schwann cells into the sciatic nerve sheath.
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Dosage form
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100 mg/kg; oral; once daily for 14 days.
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Applications
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FRAX597-treatment significantly slows tumor growth rate in mice compared to control mice. Moreover, FRAX597-treated cohort exhibits prominently lower average tumor weight compared to the control cohort.
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Other notes
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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. Licciulli S, Maksimoska J, Zhou C et al. FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas. J Biol Chem. 2013 Oct 4;288(40):29105-14.
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