2. Academic Validation
  3. Piperlongumine derivative, CG-06, inhibits STAT3 activity by direct binding to STAT3 and regulating the reactive oxygen species in DU145 prostate carcinoma cells

Piperlongumine derivative, CG-06, inhibits STAT3 activity by direct binding to STAT3 and regulating the reactive oxygen species in DU145 prostate carcinoma cells

  • Bioorg Med Chem Lett. 2018 Aug 1;28(14):2566-2572. doi: 10.1016/j.bmcl.2018.05.025.
Young Hwan Kim 1,  Yae Jin Yoon 2,  Yu-Jin Lee 2,  Cheol-Hee Kim 3,  Sangku Lee 2,  Dong Ho Choung 2,  Dong Cho Han 4,  Byoung-Mog Kwon 5
Affiliations

Affiliations

  • 1 Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea; Department of Biology, Chungnam National University, Daejeon, Republic of Korea.
  • 2 Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
  • 3 Department of Biology, Chungnam National University, Daejeon, Republic of Korea.
  • 4 Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea; Korea University of Science and Technology, Daejeon, Republic of Korea. Electronic address: dchan@kribb.re.kr.
  • 5 Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea; Korea University of Science and Technology, Daejeon, Republic of Korea. Electronic address: kwonbm@kribb.re.kr.
PMID: 29807795 DOI: 10.1016/j.bmcl.2018.05.025
Abstract

Piperlongumine (PL), isolated from Piper longum L., is receiving intense interest due to its selectively ability to kill Cancer cells but not normal cells. We synthesized a number of analogues by replacing the cyclic amide of PL with aliphatic amides to explore structural diversity. Compound CG-06 had the strongest cytotoxic profile of this series, showing potent effects in human prostate Cancer DU-145 cells, in which signal transducer and activator of transcription 3 (STAT3) is constitutively active. CG-06 inhibited STAT3 phosphorylation at tyrosine 705 in a dose- and time dependent manner in DU-145 cells and suppressed IL-6-induced STAT3 phosphorylation at Tyr-705 in DU-145 and LNCaP cell lines. CG-06 decreased the expression levels of STAT3 target genes, such as cyclin A, Bcl-2, and Survivin. Notably, we used drug affinity responsive target stability (DARTS) to show that CG-06 binds directly to STAT3, and the Reactive Oxygen Species (ROS) scavenger N-acetyl cysteine (NAC) rescued the CG-06-induced suppression p-STAT3. Our results suggest that CG-06 is a novel inhibitor of STAT3 and may be a useful lead molecule for the development of a therapeutic STAT3 Inhibitor.

Keywords

Apoptosis; Piperlongumine; Prostate cancer; ROS; STAT3.

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