In vitro: 666-15 potently inhibits cancer cell growth. In MDA-MB-231 and MDA-MB-468 cells, the GI50 for 666-15 is 73 and 46 nM, respectively. In A549 and MCF-7 cells, it exhibits robust activity as well with GI50 of 0.47 and 0.31 μM. 666-15 is also found to be a rather weak inhibitor of CREB-CBP interaction with IC50 of 18.27 μM. 666-15 inhibits CREB’s transcription activity in living cells independent of direct CREB or CBP binding interaction. 666-15 is very potent in inhibiting CREB’s transcription activity. 666-15 also inhibits endogenous CREB target gene expression, the transcript level of nuclear receptor related 1 protein (Nurr1/NR4A2). In vivo: Preliminary toxicity studies show that intraperitoneal (ip) injection of 10 mg/kg of 666-15 is well tolerated in mice. The tumor growth in the mice treated with 666-15 is efficaciously inhibited with complete tumor stasis. During the same period, the tumor volume in the vehicle-treated group is more than tripled. The body weights of 666-15-treated animals and vehicle-treated ones are indistinguishable from each other during the entire treatment period.
|Source||Sci Rep (2016). Figure 2. 666-15|
|Method||The luciferase activity assay|
|Cell Lines||HEK 293T cells|
|Incubation Time||5–7 h|
|Results||Together with previous results of 666-15’s effect on other transcription factors22, these data demonstrate that 666-15 had little or no effect on MLL, c-Myb, YAP/TEAD or p53 driven transcription, and only affected NF-κB and SRF driven transcription at concentrations ~100 fold higher than those required for CREB driven transcription.|
|Cell lines||MDA-MB-231 and MDA-MB-468 cells|
|Preparation method||Cells are plated into 96-well plates and the cells are allowed to attach to the bottom of the plates overnight. Then the cells are treated with different concentrations of different drugs (666-15) for 72 h. The media are removed, and MTT reagent in complete tissue culture media is added to each well and incubated at 37 °C for 3 h. The incubation media are removed and 100 μL of DMSO is added to each well. The absorbance of the formed purple formazan solution is read at 570 nm using a plate reader.|
|Incubation time||72 h.|
|Animal models||BALB/c nude mouse|
|Formulation||1% N-methylpyrrolidone (NMP), 5% Tween-80 in water|
|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||30 mg/mL in DMSO|
Design, synthesis and biological evaluation of regioisomers of 666-15 as inhibitors of CREB-mediated gene transcription.
Xie F, et al. Bioorg Med Chem Lett. 2017 Feb 15;27(4):994-998. PMID: 28073675.
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