Small heterodimer partner (SHP, NR0B2) is a unique orphan nuclear receptor that plays a crucial role in various metabolic processes, and is also negatively correlated with patient survival in several types of aggressive and highly metastatic human cancers. It can function as a tumor suppressor gene, and has been shown to inhibit proliferation, invasion, and migration specifically in hepatocellular carcinoma (HCC). DSHN, a small molecule probe and activator of SHP, was discovered using Small Molecule Microarray (SMM) technology. The compound stabilizes SHP by inhibiting its ubiquitination and subsequent degradation, and was shown to augment the transactivation of several known SHP activators in a dose-dependent manner (luciferase assay). The Ccl2 signaling pathway, a direct transcriptional target of SHP involved in HCC cell migration and invasion, is also blocked by DSHN through activation of SHP in vivoMol. Cancer Ther., 2016, 15(10), 2294-2301.