2. Academic Validation
  3. Design, synthesis and structure-activity relationship studies of a focused library of pyrimidine moiety with anti-proliferative and anti-metastasis activities in triple negative breast cancer

Design, synthesis and structure-activity relationship studies of a focused library of pyrimidine moiety with anti-proliferative and anti-metastasis activities in triple negative breast cancer

  • Eur J Med Chem. 2017 Nov 10:140:155-171. doi: 10.1016/j.ejmech.2017.08.067.
Dahong Yao 1,  Yuxin Zhou 2,  Lingjuan Zhu 1,  Liang Ouyang 3,  Jin Zhang 3,  Yingnan Jiang 4,  Yuqian Zhao 1,  Dejuan Sun 1,  Shilin Yang 5,  Yang Yu 6,  Jinhui Wang 1
Affiliations

Affiliations

  • 1 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, China; College of Science, China Agricultural University, No. 2 Yuanmingyuan West Road, Haidian District, Beijing 100193, China.
  • 3 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
  • 4 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China; Institute of Traditional Chinese Medicine & Natural Products, Jinan University, Guangzhou 510632, China.
  • 5 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: yangshilin@suda.edu.cn.
  • 6 Institute of Traditional Chinese Medicine & Natural Products, Jinan University, Guangzhou 510632, China. Electronic address: 1018yuyang@163.com.
PMID: 28923383 DOI: 10.1016/j.ejmech.2017.08.067
Abstract

Triple-negative breast Cancer (TNBC) is a clinical conundrum with distinct clinical and pathologic features, which is characterized by high aggression, poor prognosis, and lack of targeted therapies. In this study, based on the structural features of type II kinase inhibitors, we designed and synthesized a focused library of 41 pyrimidine derivatives possessing potent anti-proliferation activity, Y29 showed the most potent activity against MDA-MB-231 cells. Subsequently, we carried out target prediction, homology modeling, molecular docking, dynamics simulation and determination of enzymatic activity. The results suggested that PDGFR-β was its potential target. In vitro experiments revealed that Y29 attenuated metastasis by PDGFR-β inhibition-induced Autophagy and could enhance autophagy-related cell death through AKT-MAPK feedback loop in MDA-MB-231 cells.

Keywords

Autophagy; Cell death; Metastasis; Triple-negative breast cancer.

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