Background:

ALW-II-41-27 is a potent inhibitor of EPH family kinases, with an IC50 value of 11 nM to EPHA2 [1] [2].

EPH family proteins are key regulators of both disease and normal development. EPH receptors are involved in many intracellular signaling pathways such as PI3K/AKT/mTOR, RAS/RAF/MAPK, FAK, SRC, ABL, and RHO/RAC/CDC42 [2].

In H358 cells, treatment with ALW-II-41-27 at a concentration of 1 μM within 15 minutes impaired the tyrosine phosphorylation of the EPHA2 receptor and continued to inhibit the tyrosine phosphorylation through 6 hours. ALW-II-41-27 also dose-dependently inhibited the EPHA2 phosphorylation induced by ligand. When the EPHA2 was depleted by RNAi in NSCLC cell lines, cells were much less sensitive to ALW-II-41-27.

It was suggested that EPHA2 plays an oncogenic role according to results in lung cancers. In mice bearing non–small cell lung cancers (NSCLCs), intraperitoneal injection with ALW-II-41-27 at a dose of 15 mg/kg twice daily for 14 days significantly resulted in an inhibition of the growth of H358 tumors. ALW-II-41-27 significantly increased the apoptosis of tumors compared with the vehicle alone or NG-25. This was similar to the effect of the genetic ablation of EPHA2. Compared with treatments with vehicle alone or NG-25, treatment with ALW-II-41-27 did not result in significant differences in the vessel density or proliferation of tumors [2].

参考文献:
[1].  Marialuisa Moccia, Qingsong Liu, Teresa Guida, et al. Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase. PLOS ONE, 2015, 10(6):e0128364.
[2].  Katherine R. Amato, Shan Wang, Andrew K. Hastings, et al. Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC. Journal of Clinical Investigation, 2014, 124(5):2037-2049.