Rationally Designed Inhibitors Identify STAT3 N-Domain as a Promising Anticancer Drug Target

• Published in: ACS chemical biology 2007-12, Vol.2 (12), p.799-809
• Main Authors: Timofeeva, Olga A, Gaponenko, Vadim, Lockett, Stephen J, Tarasov, Sergey G, Jiang, Sheng, Michejda, Christopher J, Perantoni, Alan O, Tarasova, Nadya I
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - toxicity; Cell Survival - drug effects; Drug Design; Models, Molecular; Nuclear Magnetic Resonance, Biomolecular; Protein Structure, Tertiary; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - chemistry; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/cb700186x

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 α-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.