An investigational compound that promotes the maturation of delta F508 CFTR
VX-661, one of vertex derivatives, corrects F508del-CFTR trafficking and increases F508del-CFTR protein activity in vitro [1].
VX-661 treated alone or in combination with ivacaftor have shown to enhance F508del-CFTR traf?cking to the cell surface. VX-661 has been at phase 2 study [1].
参考文献:
[1] S. Donaldson, J. Pilewski, M. Griese, Q. Dong, P.-S. Lee, for the VX11–661-101 Study Group. WS7.3?VX-661, an investigational CFTR corrector, in combination with ivacaftor, a CFTR potentiator, in patients with CF and homozygous for the?F508Del-CFTR?mutation: Interim analysis. Journal of Cystic Fibrosis,?Volume 12, Supplement 1,?June 2013,?Page S14
| Cell experiment [1]: | |
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Cell lines |
human CF bronchial epithelial cell line CFBE41o |
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Preparation method |
The solubility of this compound in DMSO ＞21.8mg/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 |
3 μM for 24 hours at 26°C. |
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Applications |
VX-661 could partially revert the folding and processing defects and rescue PM(plasma membrane) densities of ΔF508-CFTR(Cystic fibrosis transmembrane regulator). VX-770 was a potentiators that increase channel gating and conductance.VX-770 reduced the correction efficacy of corrector VX-661. The VX-770 effect was attenuated in VX-661 treated cells, probably due to partial stabilization of the mature ΔF508-CFTR pool. A combination of chronic VX-661 and acute VX-770, together with a cAMP (cyclic adenosine 3′,5′-monophosphate) agonist, increased ΔF508-CFTR conductance to ~25% of that in non-CF HBE (human bronchial epithelial). |
| Clinical experiment [2]: | |
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Disease models |
CF (Cystic fibrosis) patients who were homozygous or heterozygous for the F508del mutation. |
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Dosage form |
10,30, 100, or 150 mg daily in oral for 28 days |
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Application |
Interim results found decreases in sweat chloride with VX-661 alone and in combination with ivacaftor(VX-770). A relative change in FEV1 (forced expiratory volume in one second) compared with placebo was significant at 28 days with VX-661 100 mg (9%) and 150 mg (7.5%) in combination with ivacaftor. |
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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] S. Donaldson, J. Pilewski, M. Griese, Q. Dong, P.-S. Lee, for the VX11–661-101 Study Group. WS7.3 VX-661, an investigational CFTR corrector, in combination with ivacaftor, a CFTR potentiator, in patients with CF and homozygous for the F508Del-CFTR mutation: Interim analysis. Journal of Cystic Fibrosis, Volume 12, Supplement 1, June 2013, Page S14 [2] National Institutes of Health. Study of VX-661 Alone and in Combination With Ivacaftor in Subjects Homozygous or Heterozygous to the F508del-Cystic Fibrosis Transmembrane Conductance Regulator(CFTR) Mutation (February 1, 2012). Available at: http://clinicaltrials.gov/ct2/show/NCT01531673. Accessed May 5, 2015. |
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