In vitro: SF2523 blocks BRD4 binding to MYCN promoter PS1/PS2. It blocks M1-M2 transition and decreases levels of p-AKT, N-MYC in several neuroblastoma cell lines. SF2523 treatment decreases protein levels of MYCN and Cyclin D1, the MYCN target, and inhibits AKT activation by blocking phosphorylation of AKT at Ser473. SF2523 interacts robustly with the full-length BRD4 (Kd = 140 nM) and exhibits comparable affinity to the BRD4 first BD (BD1) (Kd =150 nM), however it binds more weakly to the second BD (BD2) of BRD4 (Kd = 710 nM). Comparison of binding affinities of SF2523 for BDs of other proteins reveals that it binds equally well to BDs of BRD4, BRD2, and BRD3; shows moderate binding to BDs of CECR2 and BRDT; but associates much weaker with other BDs.
In vivo: SF2523 blocks spontaneous metastasis and tumor growth. SF2523 has demonstrated animal efficacy results without toxicity in the following 4 animal models: orthotopic pancreatic model, multiple myeloma model, renal cell carcinoma model, neuroblastoma xenograft model. SF2523 targets PI3K-driven and BRD4-driven oncogenic pathways in vivo. SF2523 is less toxic to the host organism in vivo than a combination of an equipotent PI3K inhibitor and BRD4 inhibitor.
|Cell lines||SKNBE2 cells|
|Preparation method||SKNBE2 cells were serum-starved for 4 h, stimulated with 50 ng/mL IGF, and used after 24 h of treatment with 1 µM JQ1, 5 µM SF2523, 10 µM SF1126, 1 μM BKM120, 1 μM BEZ235, or 200 nM CAL101 inhibitors for RNA isolation.|
|Incubation time||24 h|
|Animal models||Nude mice with xenografted tumor|
|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||29 mg/mL in DMSO|
Dual-activity PI3K–BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis
Forest H. Andrews, et al. Proc Natl Acad Sci U S A. 2017 Feb 14;114(7): E1072–E1080. PMID: 28137841.
Knockout Serum Replacement Promotes Cell Survival by Preventing BIM from Inducing Mitochondrial Cytochrome C Release.
Ishii Y, et al. PLoS One 2015 Oct 16;10(10):e0140585. PMID: 26473951.
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