生物活性

• 描述The phosphatidylinositol 3-kinase (PI3K) pathway is a major focus for drug development in various cancer due to its function as a key regulator of cell growth and survival. The bromodomain and extraterminal domain (BET) family of epigenetic “reader” proteins, including BRDT, BRD2, BRD3, and BRD4, play important roles in histone acetylation-dependent transcriptional regulation. SF2523 is a highly selective and potent inhibitor of PI3K with IC₅₀s of 34 nM, 158 nM, 9 nM, 241 nM and 280 nM for PI3Kα, PI3Kγ, DNA-PK, BRD4 and mTOR, respectively. In vitro, SF2523 decreased LPS- or IL4-induced MΘ polarization. At 500 nM, SF2523 significantly decreased mRNA expression of IL6 and iNos in LPS induced Bone marrow–derived macrophages (BMDMs) and gene expression of Arg, Tgfb, Vegf, Mmr, Ym1, and Fizz1 in IL4-induced BMDMs. In vivo, s.c. xenograft model of MYCN-amplified neuroblastoma in immunocompromised mice treated with SF2523 (50 mg/kg, three times a week) showed a significant reduction of tumor volume compared with vehicle-treated group, without gross toxicity.
• 作用机制The structure of the BRD4 BD1–SF2523 complex reveals a characteristic four-helix bundle fold of BD1, with SF2523 occupying a deep hydrophobic pocket at one of the open ends of the bundle.