IKK-16 (IKK Inhibitor VII) 是一种选择性 IκB 激酶 (IKK) 抑制剂，作用于 IKK2、IKK 复合物和 IKK1，IC50 分别为 40 nM、70 nM 和 200 nM。
IKK 16 is a selective IκB kinase (IKK) inhibitor for IKK2, IKK complex and IKK1 with IC50s of 40 nM, 70 nM and 200 nM, respectively. IKK16 also inhibits leucine-rich repeat kinase-2 (LRRK2) with an IC50 of 50 nM.
IKK 16 is a potent inhibitor of IKK2 with IC50 value of 40 nM[1]. IKK 16, a leucine-rich repeat kinase-2 (LRRK2) kinase inhibitor, exhibits in vitro IC50s of 50 nM. IKK 16 exhibits sub-micromolar IC50 concentrations for LRRK2 in vitro, which is lower than what observed for cellular inhibition of Ser935 phosphorylation. IKK 16 (20 μM) can inhibit LRRK2 Ser935 phosphorylation in HEK293 GFP-LRRK2G2019S cells (GS) or A2016T/G2019S (IRM) cells in vitro.
IKK 16 also demonstrates significant in vivo activity in an acute model of cytokine release. Both routes of administration of IKK 16 (30 mg/kg, sc) or orally (30 mg/kg, p.o) at the indicated dose results in a significant inhibition of 86% (sc) and 75% (p.o.). IKK 16(10 mg/kg, sc) is also active in the thioglycollate-induced peritonitis model in the mouse. The maximal inhibition of neutrophil extravasation in this model is about 50%[1]. Treatment of septic mice with IKK 16 (1 mg/kg body weight i.v.) results in a significantly increased degree of phosphorylation (P<0.05) of serine residues on Akt and eNOS in the liver[3].
参考文献:
[1]. Waelchli R, et al. Design and preparation of 2-benzamido-pyrimidines as inhibitors of IKK. Bioorg Med Chem Lett. Bioorg Med Chem Lett. 2006 Jan 1;16(1):108-12.
[2]. Hermanson SB, 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.
[3]. Coldewey SM, et al. Inhibition of IκB kinase reduces the multiple organ dysfunction caused by sepsis in the mouse. Dis Model Mech. 2013 Jul;6(4):1031-42.
| Cell experiment [1]: | |
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Cell lines |
HUVEC cells |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. 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 |
0.3-2μM |
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Applications |
IKK-16 (IKK Inhibitor VII) inhibited IKK2 by the blockade of IκBα degradation and suppressed TNFα-stimulated expression of the adhesion molecules E-selectin, ICAM-1, and VCAM-1 in HUVEC cells. Moreover, IKK-16 also showed activity in the IFNγ-induced expression of the MHC molecules β2 microglobulin and HLA-DR, but its potency in these assays is 4- to 10-fold weaker than the adhesion molecules assay. |
| Animal experiment [1]: | |
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Animal models |
Rat model; thioglycollate-induced peritonitis model in the mouse |
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Dosage form |
30 mg/kg, subcutaneous injection (sc) or oral administration for 5 h; or 10 mg/kg, sc |
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Applications |
IKK-16 (IKK Inhibitor VII) inhibited TNFα release into plasma upon LPS-challenge in the rat model. Moreover, IKK-16 (IKK Inhibitor VII, 10 mg/kg, sc) resulted in a maximal inhibition of neutrophil extravasation in thioglycollate-induced peritonitis model. |
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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] Waelchli R1, Bollbuck B, Bruns C, Buhl T, Eder J, Feifel R, Hersperger R, Janser P, Revesz L, Zerwes HG, Schlapbach A.Design and preparation of 2-benzamido-pyrimidines as inhibitors of IKK. Bioorg Med Chem Lett. 2006 Jan 1;16(1):108-12. Epub 2005 Oct 19. | |
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