Abstract Background: STAT3 has emerged as a novel potential anti-cancer target and its signaling is constitutively activated in various cancers including breast cancer. Our previous study has shown that STAT3 is a major kinase-independent target of sorafenib in HCC. (J Hepatol. 2011). Moreover, recent evidence has shown that p-STAT3 can be down-regulated by phosphatases, such as SHP-1 tyrosine phosphatase. We have designed and synthesized a series of sorafenib analogues devoid of sorafenib's kinase inhibition activity, some of which showed stronger p-STAT3 inhibition and apoptosis-inducing effects than sorafenib in HCC cells (Eur J Med Chem. 2011). Here, we tested the efficacy of novel sorafenib derivatives, SC-1 and SC-43, in breast cancer cells and examined the drug mechanism. Methods: Six Breast cancer cell lines were used for in vitro studies. Cell viability was examined by MTT-assay. Apoptosis was examined by both flow cytometry and Western blot. Signal transduction pathways in cells were assessed by Western Blot. SHP-1 activity was measured by a phosphatase activity assay kit. In vivo efficacy of Sorafenib, and sorafenib derivatives were tested in xenografted nude mice. Results: Sorafenib, SC-1 and SC-43 induced apoptosis in association with down-regulation of P-STAT3 and its downstream proteins Cyclin D1 and survivin in a dose-dependent manner in breast cancer cell lines (HCC-1937, MDA MB-468, MDA MB-231, MDA MB-453, SKBR-3, MCF-7) and the apoptotic effects induced by SC-1 and SC-43 were more potent than Sorafenib. Over-expression of STAT3 in MDA MB-468 cells protected cells from apoptosis induced by sorafenib, SC-1 and SC-43. Moreover, SC-1 and SC-43 up-regulated higher SHP-1 activity than sorafenib by in vitro phosphatase assays. Knockdown of SHP-1 by siRNA reduced apoptosis induced by SC-1 and SC-43. Importantly, SC-1 and SC-43 showed in vivo efficacy in MDA-468 xenografted tumor. Conclusions: Our data indicated that inhibiton of p-STAT3 by up-regulating SHP-1 activity mediated apoptotic effects of sorafenib, SC-1 and SC-43 in breast cancer cells. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-11-05.