We discovered and developed a new series of molecules (thiazole benzenesulfonamides). HA15, the lead compound of this series, displayed anti-cancerous activity on all tested melanoma cells including those isolated from patients and those that developed resistance to BRAF inhibitors. Our molecule displayed activity against other liquid and solid tumors. HA15 also exhibited strong efficacy in xenograft mouse models with melanoma cells either sensitive or resistant to BRAF inhibitors. Transcriptomic, proteomic and biochemical studies identified the chaperone BiP/GRP78/HSPA5 as the specific target of HA15 and demonstrated that the interaction increases endoplasmic reticulum (ER) stress, leading to melanoma cell death by concomitant induction of autophagic and apoptotic mechanisms. Profiling of 3 human melanoma cell lines (SKMel28, Mel501, A375) treated with HA15 at 10 uM or with DMSO was performed using whole genome human microarrays. Cells were incubated with DMSO or HA15 for 6h and then lysed prior to RNA isolation, labelling and hybridization on microarrays. One color experiment, total of 6 samples.