Rationally designed inhibitors identify STAT3 N-domain as a promising anticancer drug target.
Activation of the signal transducer and activator of transcription 3 (STAT3) is frequently detected in many cancer types. Activated STAT3 may participate in oncogenesis by stimulating cell proliferation and resisting apoptosis, as well as promoting tumor angiogenesis, invasion, and migration. Many STAT3-dependent cellular responses are mediated through interactions with other proteins, and the amino-terminal domain (N-domain) of STAT3 was proposed to be responsible for this. Our NMR studies revealed that synthetic analogs of the STAT4 second alpha-helix bind to the N-domain and perturb its structure. Structural data available for the STAT4 N-domain was used for the rational design of STAT3 helix 2 analogs with enhanced biological activity. Cell-permeable derivatives of the STAT3 second helix were found to directly and specifically bind to STAT3 but not STAT1 as determined by FRET analysis in cells expressing GFP-STAT3 and GFP-STAT1. Furthermore, they potently induced apoptotic death in breast cancer cells but not normal breast cells or STAT3-deficient fibroblasts. The inhibitors caused significant changes in the mitochondrial potential of cancer cells, leading to cell death. These compounds not only are promising drug candidates but also offer a convenient tool for studying the mechanisms of action of STAT transcription factors and have facilitated our understanding of the crucial role of the N-domain in STAT3 function.
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D017434:Protein Structure, Tertiary; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor