Sorafenib (Nexavar(R)) is the first and the lone approved targeted therapeutic agent for hepatocellular carcinoma (HCC).Previously, we found that sorafenib inhibits STAT3 through up-regulating the activity of Src homology-2 containing protein tyrosine phosphatase-1 (SHP-1).Later on,we reported that sorafenib increases SHP-1 activity by impairing the association between the N-SH2 domain and the catalytic PTP domain of SHP-1.Deletion of N-SH2 domain (dN1) or point mutation (D61A)of SHP-1 abolished the effect of sorafenib on SHP-1 activity, STAT3 phosphorylation and apoptosis.The aforementioned findings suggest that sorafenib may affect SHP-1 by triggering a conformational switch relieving its auto-inhibition.Novel sorafenib derivatives SC-60 (with a dimer-based structure) and SC-43,in which the pyridine ring and the amide group of sorafenib were substituted with phenyl cyanide, were designed to further boost SHP-1 activity.Both developed SHP-1 agonists displayed enhanced SHP-1 activity and more potent anti-HCC activity than sorafenib.SC-43 induced substantial apoptosis in sorafenib-resistant cells and showed better survival benefits than sorafenib in subcutaneous and orthotopic HCC tumors.The combination of sorafenib and SC-43, by employing two SHP-1 agonists aiming to abrogate STAT3-related signals, abolished STAT3 phosphorylation and contributed to 100% survival in the orthotopic HCC model.In conclusion, we identified SHP-1 as a major target of sorafenib.The thus developed novel SHP-1 agonists,SC-43 and SC-60, showed better anti-HCC effects than sorafenib, both in vitro and in vivo.