Alkylation of Cysteine 468 in Stat3 Defines a Novel Site for Therapeutic Development

作者：Buettner Ralf; Corzano Renzo; Rashid Rumana; Lin Jianping; Senthil Maheswari; Hedvat Michael; Schroeder Anne; Mao Allen; Herrmann Andreas; Yim John; Li Hongzhi; Yuan Yate Ching; Yakushijin Kenichi; Yakushijin Fumiko; Vaidehi Nagarajan; Moore Roger; Gugiu Gabriel; Lee Terry D; Yip Richard; Chen Yuan; Jove Richard^*; Horne David; Williams John C

来源：ACS Chemical Biology, 2011, 6(5): 432-443.

DOI：10.1021/cb100253e

Stat3 is a latent transcription factor that promotes cell survival and proliferation and is often constitutively active in multiple cancers. Inhibition of Stat3 signaling pathways suppresses cell survival signals and leads to apoptosis in cancer cells, suggesting direct inhibition of Stat3 function is a viable therapeutic approach. Herein, we identify a small molecule, C48, as a selective Stat3-family member inhibitor. To determine its mechanism of action, we used site-directed mutagenesis and multiple biochemical techniques to show that C48 alkylates Cys468 in Stat3, a residue at the DNA-binding interface. We further demonstrate that C48 blocks accumulation of activated Stat3 in the nucleus in tumor cell lines that overexpress active Stat3, leading to impressive inhibition of tumor growth in mouse models. Collectively, these findings suggest Cys468 in Stat3 represents a novel site for therapeutic intervention and demonstrates the promise of alkylation as a potentially effective chemical approach for Stat3-dependent cancers.

• 出版日期2011-5