Abstract 1166: Identification of a novel quinoxaline-isoselenourea targeting STAT3 pathway as a potential melanoma therapeutic

The prognosis for patients with metastatic melanoma remains very poor. Constitutive STAT3 activation has been correlated to larger tumor size, metastasis, acquired resistance against vemurafenib (PLX-4032), and poor patient survival suggesting its potential as a molecular target. We recently designed a series of isoseleno- and isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects of lead isoseleno-/isothio-urea derivatives (compounds 1/3) were studied in a panel of five melanoma cell lines, including B-RAFV600E mutant and wild type (WT) cells. Compound 1 (IC50 range 0.8-3.8 µM) showed lower IC50 values than 3 (IC50 range 8.1-38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC50 range 0.4->50 µM), especially at shorter treatment time (24 h). These effects are long-lasting since melanoma cells did not recover their proliferative potential after 14 days of the treatment. In addition, we confirmed that compound 1 induces cell death by apoptosis using Live and Dead, Annexin V and Caspase3/7 apoptosis assays. Furthermore, compound 1 reduces protein levels of STAT3 and its phosphorylation, as well as decreases the expression of STAT3 regulated genes involved in survival and metastasis such as survivin and c-myc. Compound 1 also upregulates the cell cycle inhibitor p21. Docking studies further revealed the favorable binding of 1 with SH2 domain of STAT3 suggesting its activity through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis by means of the inhibition of STAT3 pathway to non-specifically target both B-RAF mutant and WT melanoma cells with much better cytotoxicity than the current therapy PLX-4032. Citation Format: Verónica Alcolea, Deepkamal Karelia, Manoj K. Pandey, Daniel Plano, Parvesh Singh, Rosalyn B. Irby, Juan Palop, Shantu Amin, Carmen Sanmartín, Arun K. Sharma. Identification of a novel quinoxaline-isoselenourea targeting STAT3 pathway as a potential melanoma therapeutic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1166. doi:10.1158/1538-7445.AM2017-1166