A-1155463, a highly potent and selective BCL-XL inhibitor, shows picomolar binding affinity to BCL-XL, and >1000-fold weaker binding to BCL-2 and related proteins BCL-W(Ki=19 nM) and MCL-1(Ki>440 nM).

BCL-XL:<0.01 nM(Ki)

A-1155463在细胞中破坏BCL-XL-BIM复合体，但不影响BCL-2-BIM复合体。对于依赖BCL-XL的Molt-4细胞，A-1155463具有杀伤作用（EC50=70 nM），而对于依赖BCL-2的RS4;11细胞，则没有明显的细胞毒性（EC50>5 mM）。A-1155463能诱导凋亡的典型特征，包括线粒体释放细胞色素c、激活caspase以及BCL-XL依赖的H146细胞中caspase依赖的sub-G0-G1 DNA含量的积累。

在非肿瘤SCID-Beige小鼠体内，单次以5 mg/kg IP方式给予A-1155463后，观察到血小板数量在给药后6小时内急剧下降，而后在72小时内恢复至正常水平。连续每日以5 mg/kg IP剂量对已接种BCL-XL依赖型H146肿瘤细胞的SCID-Beige小鼠进行14天治疗，显示出肿瘤生长受到统计学上显著的抑制（最大肿瘤生长抑制率=44%），该抑制效果在停药后消失[1]。

Recombinant p38 isoforms are activated by Mkk6(E) under the following conditions: p38 (100 ng/mL), Mkk6(E) (30 ng/mL), ATP (100 mM) are mixed in kinase buffer (25 mM Hepes, 25 mM b-glycerophosphate, 0.1 mM sodium orthovanadate, 25 mM MgCl2, 2.5 mM DTT, pH 7.4) and incubated for 30 min at 30°C. A typical assay reaction for Mnk1 activity contained Mnk1 (2 ng/mL), HA-eIF4E (10 ng/mL), ATP (300 mM) in kinase buffer. The reaction is started by addition of activated p38 (0.03-3 ng/mL) and stopped after 30 min at 30°C by addition of SDS loading buffer. Inhibitors of Mnk1 are identified under the same assay conditions, except that Mnk1 is pre-activated using active p38a before exposure to the substrate and inhibitors.

Cells are treated with increasing concentration of A-1155463. Cells are assayed for viability after 72 h using the CellTiter-Glo luminescent cell viability assay according to the manufacturer's protocol. Results are normalized to cells without treatment. EC50 is calculated using the GraphPad Prism software.(Only for Reference)

Animal Models: SCID-Beige MiceFormulation: 5% DMSO, 10% EtOH, 20% Cremaphor ELP, and 65% D5WDosages: 5 mg/kgAdministration: i.p.