2. Academic Validation
  3. Novel 2-Carbonylbenzo[b]thiophene 1,1-Dioxide Derivatives as Potent Inhibitors of STAT3 Signaling Pathway

Novel 2-Carbonylbenzo[b]thiophene 1,1-Dioxide Derivatives as Potent Inhibitors of STAT3 Signaling Pathway

  • ACS Med Chem Lett. 2015 Jul 27;6(9):1010-4. doi: 10.1021/acsmedchemlett.5b00228.
Peng Ji 1,  Xin Xu 2,  Shuhua Ma 3,  Junchao Fan 1,  Qiang Zhou 1,  Xinliang Mao 2,  Chunhua Qiao 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, College of Pharmaceutical Science, Soochow University , 199 Ren Ai Road, Suzhou 215123, P. R. China.
  • 2 Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University , Suzhou 215123, P. R. China.
  • 3 Department of Chemistry, Jess and Mildred Fisher College of Science and Mathematics, Towson University , 8000 York Road, Towson, Maryland 21252, United States.
  • 4 Department of Medicinal Chemistry, College of Pharmaceutical Science, Soochow University , 199 Ren Ai Road, Suzhou 215123, P. R. China ; Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho-diseases, Department of Pharmacology, College of Pharmaceutical Sciences, and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University , Suzhou 215123, P. R. China.
PMID: 26396689 DOI: 10.1021/acsmedchemlett.5b00228
Abstract

Signal transducer and activator of transcription 3 (STAT3) is considered to be an attractive therapeutic target for Cancer therapy. In this study, a series of 2-carbonylbenzo[b]thiophene 1,1-dioxide derivatives (CBT) were designed to inhibit the STAT3 SH2 domain phosphorylation site Try 705. We demonstrated that incorporation of basic flexible groups through amide bond linkage to benzo[b]thiophene 1,1-dioxide (BTP) achieved compounds with higher antiproliferative potency than BTP itself. The most potent compound 6o, as indicated from luciferase reporter gene assay, inhibited the STAT3 pathway by decreasing the phosphorylation level of STAT3 Tyr705, while the phosphorylation level of Other upstream tyrosine kinases in this pathway was not significantly inhibited. Compound 6o was also shown to trigger ROS generation and accumulation, thus consequently attributed partially to the observed cell Apoptosis. This study provided important structural information for the development of inhibitors targeting the STAT3 pathway.

Keywords

2-carbonylbenzo[b]thiophene 1,1-dioxide derivatives; STAT3; antiproliferative activity; apoptosis; inhibitor; reactive oxygen species.

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