2. Academic Validation
  3. Identification of new shikonin derivatives as STAT3 inhibitors

Identification of new shikonin derivatives as STAT3 inhibitors

  • Biochem Pharmacol. 2017 Dec 15:146:74-86. doi: 10.1016/j.bcp.2017.10.009.
Han-Yue Qiu 1,  Jiang-Yan Fu 1,  Min-Kai Yang 1,  Hong-Wei Han 1,  Peng-Fei Wang 2,  Ya-Han Zhang 1,  Hong-Yan Lin 1,  Cheng-Yi Tang 1,  Jin-Liang Qi 1,  Rong-Wu Yang 1,  Xiao-Ming Wang 3,  Hai-Liang Zhu 4,  Yong-Hua Yang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing 210023, China.
  • 3 State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address: wangxm07@nju.edu.cn.
  • 4 State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing 210023, China. Electronic address: zhuhl@nju.edu.cn.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address: yangyh@nju.edu.cn.
PMID: 29066190 DOI: 10.1016/j.bcp.2017.10.009
Abstract

The signal transducer and activator of transcription 3 is a constitutively activated oncogenic protein in various human tumors and represents a valid target for Anticancer drug design. In this study, we have achieved a new type of STAT3 inhibitors based on structural modifications on shikonin scaffold, guided by computational modelling. By tests, PMMB-187 exhibited a more outstanding profile than shikonin on a small panel of human breast Cancer cells, especially for the MDA-MB-231 cells. For the cellular mechanisms research, PMMB-187 was found to induce cell Apoptosis in MDA-MB-231 cells, associated with the reduction of mitochondrial membrane potential, production of ROS and alteration of the levels of apoptosis-related proteins. Furthermore, PMMB-187 inhibited constitutive/inducible STAT3 activation, transcriptional activity, nuclear translocation and downstream target genes expression in STAT3-dependent breast Cancer cells MDA-MB-231. Besides, no obvious inhibitory effect on activation of STAT1 and STAT5 was observed with PMMB-187 treatment. Most notably, the in vivo studies further revealed that PMMB-187 could dramatically suppress the MDA-MB-231 cells xenografted tumor growth. The in vitro and in vivo results collectively suggest that PMMB-187 may serve as a promising lead compound for the further development of potential therapeutic anti-neoplastic agents.

Keywords

Anti-neoplastic; Breast cancer; Napabucasin (PubChem CID: 10331844); Plumbagin (PubChem CID: 10205); STA-21 (PubChem CID: 363709); STAT3 inhibitors; Shikonin; Shikonin (PubChem CID: 479503); Structural modifications.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-164521
    STAT3 Inhibitor