Alternative ways of modulating JAK-STAT pathway

Abstract

Most attempts to develop inhibitors of STAT transcription factors target either activating phosphorylation of tyrosine residue or SH2 domains. However, all six domains of STATs are highly conserved between the species and play important roles in the function of this family of transcription factors. STATs are involved in numerous protein-protein interactions that are likely to regulate and fine tune transcriptional activity. Targeting these interactions can provide plentiful opportun-ities for the discovery of novel drug candidates and powerful chemical biology tools. Using N-terminal domains as an example we describe alternative rational approaches to the development of modulators of JAK-STAT signaling. STAT proteins are latent cytoplasmic transcription factors activated by tyrosine phosphorylation in response to extracellular signals and are involved in many different regulatory events. 1 In mammals, the STAT family consists of STAT1, 2, 3, 4, 5A, 5B and 6, and shares a common set of structural domains: N-terminal, coiled-coil, DNA binding, SH2, linker and transactiva-tion domains. 2 The mammalian STAT family is implicated in responses to cytokines and growth factors, and exert diverse effects on a number of biological processes including immunity, hematopoiesis, inflammation and development. 3