Correlating their inhibitory potencies with the pharmacophore model gave information about probable binding modes. Ocular melanomas represent approximately 5% of all melanomas, with a majority of these being uveal in origin. Uveal melanoma is the most common primary intraocular malignant tumor in adults, with an annual incidence of seven cases per million. Approximately 50% of UM patients develop metastatic melanoma to the liver within 15 years of initial diagnosis. With distant metastases, there currently is no effective treatment modality. The median survival for UM patients with metastasis is less than six months. The etiology of UM has not been fully understood. Although uveal and cutaneous melanomas arise from the same cell type, they have distinct genetic alterations. Genetic mutations in the TP53, BRAF, RAS, CDKN2 and PTEN genes are common in cutaneous melanoma but rare in UM. Drugs commonly used to treat cutaneous melanoma seldom produce durable responses in UM patients. The preponderance of liver metastases in uveal melanoma patients has focused therapeutic effort in local control of metastatic disease for palliation. Recently, somatic mutations in the GNAQ gene have been identified in about 50% of UM and 83% blue naevi. GNAQ mutations occurring at codon 209 of the RAS-like domain result in constitutive activation of the MAPK/Erk1/2 pathway in melanocytes and confer dominantly acting oncogenic functions to GNAQ. The GNAQ gene encodes for the a subunit of q class of heterotrimeric GTP binding protein that mediates signals from G-protein-coupled receptors and stimulates all four isoforms of b phospholipase C. PLCb enzymes catalyze the hydrolysis of phosphatidylinositol biphosphate, to release inositol trisphosphate and diacylglycerol that function as second messengers and propagate and amplify the Ga-mediated signal through stimulation of protein kinase C. It has been hypothesized that signaling from GNAQ to MAPK/Erk1/2 is transmitted through DAG/ PKC. The PKC family is a widely expressed group of serine/ threonine kinases comprising at least twelve isoforms. PKCs are involved in key cellular processes including cell proliferation, apoptosis, and differentiation. Increased PKC expression and activity have been demonstrated in many cancers. PKCs may play important roles in tumor formation and 
progression, invasiveness of cancer cells, and chemoresistance. The mechanisms by which PKCs contribute to tumorigenesis, however, are not fully understood. Enzastaurin is a potent and selective competitive inhibitor of PKCb at low concentrations and AZD6244 inhibits other PKC isoenzymes at ALK5 Inhibitor II higher concentrations. In addition, enzastaurin targets the phosphatidylinositol 3-kinase/ AKT pathway, and inhibits phosphorylation of GSK3b and ribosomal protein S6. Although enzastaurin was initially developed as an antiangiogenic agent, it also has direct proapoptotic and antiproliferative activities on various human cancer cells. Therefore, enzastaurin may exhibit antitumor activity through multiple mechanisms affecting both tumor angiogenesis and apoptosis. Given the importance of PKC in tumorigenesis and potentially in GNAQ mutation-induced MAPK activation, we hypothesized that PKC may provide new opportunities for therapeutic intervention of UM carrying GNAQ mutations. In the present study, we tested this hypothesis by examining the response of UM cells with wild type or mutant GNAQ toward the antiproliferative and proapoptotic action of enzastaurin and characterized the underlying signaling and molecular mechanisms. The statistical model results indicate that the effect of enzastaurin upon viability depends upon both the mutational status and enzastaurin concentration.