生物活性

• 靶点	Axl IC50:14nM

• 描述Axl is a member of the TAM (Tyro3, Axl, Mer) receptor tyrosine kinase (RTK) family and Axl signaling stimulates cellular responses and results in invasion, migration, survival signaling, angiogenesis, cell transformation, and proliferation associated with cancer. R428 (BGB324) is an inhibitor of Axl with IC50 of 14 nM by blocking the catalytic and procancerous activities with low nanomolar activity. R428-treated tumors reduce expression of the cytokine granulocyte macrophage colony-stimulating factor and angiogenesis in corneal micropocket and tumor model as well as metastatic burden and extends survival in MDA-MB-231 intracardiac and 4T1 orthotopicmouse models of breast cancer. The mean IC50 for the primary CLL B cells is of ~2.0 μM of R428 treatment and no significant amount of cell death of normal B-, T-, natural killer (NK) cells were observed at this dose of 2.5 μM. R428 inhibited Axl phosphorylation by 50%-60% in CLL B cells at a dose of 1.0 μM for overnight suggesting R428 can target Axl phosphorylation and are responsible for apoptosis induction in CLL B cells. Furthermore, a substantial level of reduction in Mcl-1 in all the 3 CLL B-cell lysates (P5-P7) treated with R428 in both a dose- and time dependent manner. Besides, R428 inhibited growth of H1299 with an IC50 of approximately 4 μM while LDC1267 had no effects on the cell growth even at 20 μM. R428 induced a series of apoptotic events, including caspase-8/9 activation, PARP cleavage, and upregulation of anti-apoptotic proteins Bcl-xl and Bcl-2 in the Hela cells. R428 treatment also increased the autophagy level of LC3-II, indicating the induction of autophagy initiation, but did not decrease the level of p62, suggesting a blockage of autophagic degradation. Further analyses revealed that R428 blocked lysosomal acidification and recycling, accumulated autophagosomes and lysosomes, and induced cell apoptosis.

• 动物研究
  剂量	Nude Mice: 7 mg/kg - 125 mg/kg[3] (p.o.) BALB/c Mice: 7 mg/kg - 75 mg/kg[3] (p.o.) C57BL/6 Mice: 50 mg/kg, 100 mg/kg[4] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Mice[3] Dose 75 mg/kg Administration p.o. Cmax 6.8 µmol/l T1/2 13 h