Abstract
With the aim to discover new STAT3 direct inhibitors, potentially useful as anticancer agents, a set of methanethiosulfonate drug hybrids were synthesized. The in vitro tests showed that all the thiosulfonic compounds were able to strongly and selectively bind STAT3-SH2 domain, whereas the parent drugs were completely devoid of this ability. In addition, some of them showed a moderate antiproliferative activity on HCT-116 cancer cell line. These results suggest that methanethiosulfonate moiety can be considered a useful scaffold in the preparation of new direct STAT3 inhibitors. Interestingly, an unusual kind of organo-sulfur derivative, endowed with valuable antiproliferative activity, was occasionally isolated.
Highlights
Signal transducer and activator of transcription 3 (STAT3) were identified in 1994 as a DNA-binding factor that selectively interacts with IL-6-responsive element in the promoter of acute-phase genes from IL-6-stimulated hepatocytes[1]
Upon phosphorylation in the cytoplasm, STAT3 can dimerize forming homodimers or heterodimers through specific reciprocal Src homology 2 (SH2)-phosphotyrosine interaction; the dimers translocate into the nucleus, bind to specific DNA-binding elements, and activate transcription of target genes, which are mainly involved in cell proliferation, differentiation, apoptosis, and inflammation[3]
STAT3 was found to be constitutively activated by aberrant upstream tyrosine kinase activity in a broad spectrum of cancer cell lines and human tumors, and it is considered a promising target for cancer therapy
Summary
Signal transducer and activator of transcription 3 (STAT3) were identified in 1994 as a DNA-binding factor that selectively interacts with IL-6-responsive element in the promoter of acute-phase genes from IL-6-stimulated hepatocytes[1]. STATs directly transmit signals from plasma membrane to the nucleus and regulate cell growth and survival by modulating the expression of specific target genes. This family comprises seven isoforms, namely STAT1 to STAT4, STAT5a, STAT5b, and STAT62, that present several structurally and functionally conserved domains including the Src homology 2 (SH2) domain which is essential for the activation cascade pathway. Several studies confirmed that STAT3 inhibitors have minimal effects on normal cells[4,5], providing the potential for selective tumor cell elimination
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