In vitro activity: SF2523 is a novel, selective and potent dual inhibitor of PI3K-BRD4 with IC50s of 34 nM, 158 nM, 9 nM, 241 nM and 280 nM for PI3Kα, PI3Kγ, DNA-PK, BRD4 and mTOR, respectively. 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. Dual-action inhibitor SF2523 impairs PI3K/BRD4 signaling in vitro and in vivo and affords maximal MYC down-regulation. The concomitant inhibition of PI3K and BRD4 blocks MYC expression and activation, promotes MYC degradation, and markedly inhibits cancer cell growth and metastasis. Collectively, these findings suggest that the dual-activity inhibitor represents a highly promising lead compound for the development of novel anticancer therapeutics.

Kinase Assay: SF2523 is a novel, selective and potent dual inhibitor of PI3K-BRD4 with IC50s of 34 nM, 158 nM, 9 nM, 241 nM and 280 nM for PI3Kα, PI3Kγ, DNA-PK, BRD4 and mTOR, respectively.

Cell Assay: SKNBE2 cells are serum-starved for 4 h, stimulated with 50 ng/mL IGF, and treated with 1 μM JQ1, 5 μM SF2523, 10 μM SF1126, 1 μM BKM120, 1 μM BEZ235, or 200 nM CAL101 for 24 h. Then, cells are harvested and total RNA is extracted; Perform RT-PCR.

Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):E1072-E1080. /10.1021/acs.jmedchem.6b00438