生物活性

• 靶点	PI3Kδ EC50:24.3nM

• 描述Phosphoinositide-3 kinase (PI3K) is a kind of intracellular lipid kinase that frequently been activated in human cancers and thus been an attractive target. PI3K contains PI3Kα, β, δ and γ isoforms and RP-5264 is the inhibitor of PI3Kδ with IC₅₀ value of 22.2 nM and EC50 value of 24.3 nM. RP-5264 could induce anti-FceR1 induced CD63 surface expression with EC₅₀ value of 67nM as well as significant inhibit CD19+ or CD45R+ cell proliferation with concentration of 1000 nM. In multiple Myeloma resistant or sensitive cells, the drug showed IC50 values of 2975 and 3157 nM respectively. Furthermore, 50 mg/kg RP-5264 led to 80% inhibition of LPS induced CD45R in mice model. And 40% inhibitions of HL-60, THP-1, MOLT-4 and DLBCL cells were observed when treated with 300 nM RP-5264^[1]. In L-540, KM-H2 and L-428 cells, RP-5264 could inhibit their proliferations and survivals with IC₅₀ values of 11, 16 and 46 μM respectively. Furthermore, cell death in L-540 cells was significantly increased and modest cytotoxic effect was observed in KM-H2 and L-428 cells after exposure for longer time. RP-5264 could also quickly inhibit constitutive phosphorylation of Akt within one hour. When 10 μM RP-5264 combined with 10 ng/ml BV was used, a significant reduction of the cell proliferation and an increasing of apoptotic cell death in these cell lines were observed and accompanied by down-regulation of anti-apoptotic proteins Mcl-1 and Bcl-2. Besides, the combination of the two drugs also induced a marked G2/M accumulation and G0/G1 reduction, suggesting an early G2/M arrest followed by apoptotic cell death. Such an combined treatment could also increase cyclin A2 and CDK1 levels as well as phospho-CDK1, MPM-2 and phosphor-histone H3, and so did the microtubule assembly^[2].

• 动物研究
  剂量	Mice: 20 mg/kg[3] (p.o.), 100 mg/kg[4] (p.o.)
  给药途径	p.o.