765 HCV CORE PROTEIN MODULATES TGF-ß RESPONSES IN AN AUTOCRINE AND PARACRINE MANNER, A NOVEL PARADIGM FOR THE INTERPLAY BETWEEN HOST- AND VIRAL-RELATED CARCINOGENETIC SIGNALS

Abstract

Results: GSK2336805 has EC50 values of 44 pM, 8 pM and 54 pM on genotype 1a, 1b and 2a (JFH-1) replicons, respectively and 63 pM on the HCVcc virus (JFH-1). CC50 values were be 43 and 47 mM on genotype 1a and 1b replicons respectively, yielding a selectivity index 1000. Long term exposure of genotype 1b replicon cells to GSK2336805 to 3-fold and 10-fold EC90 concentrations resulted in 3 and 4 log reductions, respectively, in replicon RNA levels. Resistance maps to the NS5A gene and cross resistance profiling showed that GSK2336805A is not cross resistant to mutations altering the potency of DAAs targeting NS3, NS4B, and NS5B as well as a mutation impacting cyclophillin inhibitors. Profiling on chimeric replicons containing NS5A patient sequences for genotype 1a and genotype 1b showed GSK2336805 retained potency across the subtypes with only one chimera showing a change in potency. The compound is also a potent inhibitor of chimeric replicons containing NS5A consensus and patient sequences from genotypes 28–6. Combination studies showed that GSK2336805 is not antagonistic with interferon, ribavirin, cyclosporine A, or with DAAs targeting NS3, NS4B, or NS5B. This data set supports inclusion of GSK2336805 as part of a combination regimen to treat HCV infected individuals.