We describe a de novo computational approach for designing proteins that recapitulate the binding sites of natural cytokines, but are otherwise unrelated in topology or amino acid sequence. We use this strategy to design mimics of the central immune cytokine interleukin-2 (IL-2) that bind to the IL-2 receptor beta gamma c heterodimer (IL-2R beta gamma c) but have no binding site for IL-2R alpha (also called CD25) or IL-15R alpha (also known as CD215). The designs are hyper-stable, bind human and mouse IL-2R beta gamma c with higher affinity than the natural cytokines, and elicit downstream cell signalling independently of IL-2R alpha and IL-15R alpha. Crystal structures of the optimized design neoleukin-2/15 (Neo-2/15), both alone and in complex with IL-2R beta gamma c, are very similar to the designed model. Neo-2/15 has superior therapeutic activity to IL-2 in mouse models of melanoma and colon cancer, with reduced toxicity and undetectable immunogenicity. Our strategy for building hyperstable de novo mimetics could be applied generally to signalling proteins, enabling the creation of superior therapeutic candidates.