生物活性

• 靶点	HSP90 IC50:24nM

• 描述Heat shock protein 90 (HSP90) is a molecular chaperone responsible for maintaining proteostasis in cells. XL888 is a HSP90 inhibitor with an IC50 value of 24 nM. In NCI-N87 cells, XL888 resulted in HER2 degradation with an IC50 value of 56 nM. In NCI-N87, BT-474, and MDA-MB-453 cell lines overexpressing HER2, the proliferation IC50 values were 21.8, 0.1, and 16.0 nM, respectively. In Colo-205, SK-MEL-28 cell lines with B-Raf mutation, the proliferation IC50 values were 11.6 and 0.3 nM, respectively^[3]. When WM-266-4 cells were treated with 370 nM XL888 for 24h, the number of cells at S phase was decreased and the 4N DNA content in cells were accumulated compared to DMSO-treated cells. The incubation of MCF-7 cells with XL888 (35 – 556 nM) for 24h resulted in a significant reduction in S phase accompanied with an increase in M (+/-G2). After the treatment with 123 nM XL888 for 18h, CHL-1 cells showed M phase arrest with highly organized chromosomes in a linear, metaphase-like configuration compared to DMSO-treated group. In two M-class lines (CHL-1 and EBC-1), XL888 at 14 – 1670 nM dose-dependently decreased PLK1 level after 4 – 12h post treatment^[4]. In NCI-N87 xenograft mouse model, XL888 treatment at 60 mpk (once per day) led to 100% tumor growth inhibition 27d post implantation, whereas dosing at 100 mpk (once per day for 3 days, every 7 days) exceeded 100% tumor growth inhibition and demonstrated 21% tumor regression^[3].
• 作用机制XL888 inhibits HSP90 in an ATP-competitive mode^[3].

• 动物研究
  剂量	Mice: 100 mg/kg[2] (p.o.)
  给药途径	p.o.