In vitro: Y2409881 inhibited constitutively activated NF-κB, and caused concentration- and time-dependent growth inhibition and apoptosis in lymphoma cells. Pretreatment of LY10 with 10 umol/L of LY2409881 prevented the formation of phosphorylated IkB in samples treated with TNFa for 2, 20, and 60 minutes in the presence of abundant IkB protein. In vivo: LY2409881 was safe to mice at three dose levels, 50, 100, and 200 mg/kg, all of which caused significant inhibition of tumor growth. LY2409881 suppressed the activity of the NF-κB subunit p65 in lymphoma cells treated by the HDAC inhibitor romidepsin, underlying a potential mechanism of the marked synergy observed of these two drugs.
|Source||Clin Cancer Res (2015). Figure 2. LY2409881|
|Method||Vybrant Apoptosis Assay|
|Cell Lines||SUDHL2 cells|
|Concentrations||10 and 20 μmol/L|
|Incubation Time||24 h|
|Results||These results confirm that LY2409881 inhibits constitutively activated NF-κB, leading to cell death in B- and T-cell lymphoma cell lines.|
|Cell lines||DLBCL cell line|
|Preparation method||After incubation with LY2409881for 4 hours, the samples were placed on the slides using the Cytospin. After fixation in 10% formalin and 100% methanol, the slides were transferred to the blocking buffer (10% nonfat dry milk) and incubated with primary antibody in the humidity chamber overnight.|
|Incubation time||4 h|
|Animal models||SCID beige mice|
|Formulation||5% dextrose in wate|
|Dosages||50 mg/kg, 100 mg/kg, 200 mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||37 mg/mL in DMSO|
The novel IKK2 inhibitor LY2409881 potently synergizes with histone deacetylase inhibitors in preclinical models of lymphoma through the downregulation of NF-κB.
Deng C, et al. Clin Cancer Res. 2015 Jan 1;21(1):134-45. PMID: 25355930.
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