生物活性

• 描述B cell lymphoma 6 (BCL6) is a transcriptional repressor required for B cells to form germinal centers (GCs) during the humoral immune response. The translocations and amplifications of the BCL6 locus are one of the hallmarks of activated B cell diffuse large B cell lymphomas (ABC-DLBCLs). FX1 potently and specificly inhibits BCL6 with an IC50 of 35 μM. The activity of FX1 was measured against a panel of 50 different kinases at concentration of 10 μM. FX1 failed to significantly inhibit of any of these kinases confirming its selectivity over BCL6. Quantitative ChIP assays were performed in DLBCL cells exposed to 50 μM FX1 for 30 minutes. FX1 profoundly reduced recruitment of BCOR and SMRT to all 3 BCL6 target genes, but not at a negative control locus (P < 0.001). In DLBCL cells, FX1 almost invariantly induced significant derepression of BCL6 target genes as compared with vehicle. In immunized C57BL/6 mice treated with FX1 (80 mg/kg; 10 d), GC B cells (GL7⁺FAS⁺B220⁺) were significantly depleted by exposure to FX1 (P < 0.0001) which was similar to the BCL6 BTB mutant phenotype. SCID mice with DLBCL xenografts were initially treated with 25 mg/kg FX1 daily. FX1 caused profound and significant suppression of DLBCLs (P = 0.001), and indeed not only prevented growth of the xenografts but in addition caused these tumors to shrink from their initial volume.
• 作用机制FX1 binds to the BCL6 BTB lateral groove.

• 动物研究
  剂量	C57BL/6 mice: 25 mg/kg[1] (i.p.), 80 mg/kg[2] (i.p.) BALB/c: 100 mg/kg[2] (i.p.) Macaque: 10 mg/kg, 25 mg/kg[3] (s.q.)
  给药途径	i.p., s.q.
  动物药代数据	Animal Mice[3] Monkeys[3] Dose 25 mg/kg 25 mg/kg Administration i.p. s.q. T1/2 9.51 h 3.37 h Tmax 0.5 h 2 h Cmax 7000 nM/ml 155 nM/ml AUC0→t 47300 nM·h/ml 821.3 nM·h/ml