2. Academic Validation
  3. Design and synthesis of novel Flavone-based histone deacetylase inhibitors antagonizing activation of STAT3 in breast cancer

Design and synthesis of novel Flavone-based histone deacetylase inhibitors antagonizing activation of STAT3 in breast cancer

  • Eur J Med Chem. 2020 Nov 15;206:112677. doi: 10.1016/j.ejmech.2020.112677.
Mingming Wei 1,  Maodun Xie 1,  Zhen Zhang 1,  Yujiao Wei 1,  Juan Zhang 2,  Hongli Pan 3,  Benlong Li 1,  Jingjing Wang 1,  Yang Song 1,  Chuangke Chong 1,  Rui Zhao 1,  Jiefu Wang 4,  Li Yu 5,  Guang Yang 6,  Cheng Yang 7
Affiliations

Affiliations

  • 1 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China.
  • 2 Department of Hematology and Oncology, International Cancer Center, Shenzhen University General Hospital, Shenzhen University Health Science Center, Xueyuan AVE 1098, Nanshan District, Shenzhen, Guangdong, 518000, PR China.
  • 3 Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, PR China.
  • 4 Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, PR China. Electronic address: jwang05@tmu.edu.cn.
  • 5 Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, PR China. Electronic address: liyu301@vip.163.com.
  • 6 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China. Electronic address: Guang.yang@nankai.edu.cn.
  • 7 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin, 300071, PR China. Electronic address: Cheng.yang@nankai.edu.cn.
PMID: 32823005 DOI: 10.1016/j.ejmech.2020.112677
Abstract

Histone deacetylases (HDACs) inhibitors have demonstrated a great clinical achievement in hematological malignancies. However, the efficacy of HDACs inhibitors in treating solid tumors remains limited due to the complicated tumor microenvironment. In this study, we designed and synthesized a class of novel HDACs inhibitors based on the structure of Flavones and Isoflavones, followed by biological evaluation. To be specific, a lead compound 15a was discovered with strong anti-proliferative effects on a variety of solid tumor cells, especially for breast Cancer cells with resistance to SAHA. Studies demonstrated that 15a could significantly inhibit the activity of HDAC 1, 2, 3 (class I) and 6 (class IIB), leading to a dose-dependent accumulation of acetylated histones and α-Tubulin, cell cycle arrest (G1/S phase) and Apoptosis in breast Cancer cells. Furthermore, the lead compound 15a could also antagonize the activation of STAT3 induced by HDACs inhibition in some breast Cancer cells, which further reduced the level of pro-survive proteins in tumor cells and enhanced anti-tumor activity regulated by STAT3 signaling in vivo. Overall, our findings demonstrated that the novel compound 15a might be a HDACs inhibitor candidate, which could be used as promising chemotherapeutic agent for breast Cancer.

Keywords

Flavones; HDAC; Hybrid; STAT3 signaling pathway; Solid malignancies.

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