The disclosure provides methods and compositions for identifying agents that inhibit a neoplastic cellular phenotype mediated by the NS4B protein nucleotide binding motif (NBM) of hepatitis C virus (HCV). In general, the methods involve contacting a candidate agent with a mammalian cell expressing an NS4B NBM polypeptide of an HCV virus, wherein expression of the NS4B NBM polypeptide in the absence of candidate agent promotes a neoplastic cellular phenotype, and detecting the presence or absence of an effect of said candidate agent on NS4B-mediated promotion of a neoplastic cellular phenotype. The disclosed methods and compositions find use in a variety of therapeutic and screening applications.