HA15 is a molecule that targets specifically BiP/GRP78/HSPA5. HA15 displays anti-cancerous activity on all melanoma cells tested, including cells isolated from patients and cells that developed resistance to BRAF inhibitors.
HA15 is a thiazole benzensulfonamide that specifically targets the endoplasmic reticulum chaperone BiP. Treatment of human melanoma cell lines with 10μM of HA15 for 6 hours decreased cell viability compared with the DMSO-treated controls. The IC50 value of HA15 for the viability of A375 cells was between 1 and 2.5μM. Treatment of A375 cells with HA15 (10μM) for 4 hours greatly induced the expression of IRE1α, ATF4, and CHOP. Also, PERK and elF2α remained phosphorylated in HA15-treated cells. HA15 at 1 – 100μM significantly inhibited the ATPase activity of BiP in a dose-dependent manner. HA15 at a concentration of 10μM increased the levels of cleaved and activated form of caspase 9, and led to the cleavage of PARP in A375 cells. In mice inoculated with A375 cells, administration of HA15 (0.7mg/day) for 2 weeks markedly suppressed tumor growth without inducing hepatic toxicity.[2]
作用机制
HA15 induced a dissociation between the BiP, PERK, IRE1α, and ATF6 complex. It inhibits the activity of BiP activity by directly binding to it. HA15 inhibits tumor growth in vivo through ER stress-induced autophagy and apoptosis.[2]
搜索
