The signal transducer and activator of transcription 3 is a constitutively activated oncogenic protein in various human tumors and represents a valid target for anticancer drug design.In this study,we have achieved a new type of STAT3 inhibitors based on structural modifications on shikonin scaffold,guided by computational modelling.By tests,PMMB-187 exhibited a more outstanding profile than shikonin on a small panel of human breast cancer cells,especially for the MDA-MB-231 cells.For the cellular mechanisms research,PMMB-187 was found to induce cell apoptosis in MDA-MB-231 cells,associated with the reduction of mitochondrial membrane potential,production of ROS and alteration of the levels of apoptosis-related proteins.Furthermore,PMMB-187 inhibited constitutive/inducible STAT3 activation,transcriptional activity,nuclear translocation and downstream target genes expression in STAT3-dependent breast cancer cells MDA-MB-231.Besides,no obviously inhibitory effect on activation of STAT1 and STAT5 was observed with PMMB-187 treatment.Most notably,the in vivo studies further revealed that PMMB-187 could dramatically suppress the MDA-MB-231 cells xenografted tumor growth.The in vitro and in vivo results collectively suggest that PMMB-187 may serve as a promising lead compound for the further development of potential therapeutic anti-neoplastic agents.