2. Academic Validation
  3. Targeting BRK-Positive Breast Cancers with Small-Molecule Kinase Inhibitors

Targeting BRK-Positive Breast Cancers with Small-Molecule Kinase Inhibitors

  • Cancer Res. 2017 Jan 1;77(1):175-186. doi: 10.1158/0008-5472.CAN-16-1038.
Jie Jiang 1,  Fu Gui 1,  Zhixiang He 1,  Li Li 1,  Yunzhan Li 1,  Shunying Li 2,  Xinrui Wu 1,  Zhou Deng 1,  Xihuan Sun 1,  Xiaoxing Huang 1,  Wei Huang 1,  Shang Han 1,  Ting Zhang 1,  Zheng Wang 1,  Bo Jiao 3,  Siyang Song 1,  Hongrui Wang 1,  Lanfen Chen 1,  Dawang Zhou 1,  Qiang Liu 2,  Ruibao Ren 4 5,  Jianming Zhang 6,  Xianming Deng 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
  • 2 Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3 State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Collaborative Innovation Center of Hematology, Collaborative Innovation Center of System Biology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Collaborative Innovation Center of Hematology, Collaborative Innovation Center of System Biology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. xmdeng@xmu.edu.cn Jzhang14@mgh.harvard.edu ren@brandeis.edu.
  • 5 Department of Biology, Brandeis University, Waltham, Massachusetts.
  • 6 Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. xmdeng@xmu.edu.cn Jzhang14@mgh.harvard.edu ren@brandeis.edu.
  • 7 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. xmdeng@xmu.edu.cn Jzhang14@mgh.harvard.edu ren@brandeis.edu.
PMID: 27758886 DOI: 10.1158/0008-5472.CAN-16-1038
Abstract

Approximately 80% of breast cancers overexpress the kinase Breast Tumor Kinase (BRK)/protein tyrosine kinase 6, which has various oncogenic roles in breast Cancer cell proliferation, survival, and migration. However, BRK inhibitors have yet to be explored as possible therapeutic tools. In this study, we used a parallel compound-centric approach to discover a new class of pharmaceutical agents, exemplified by XMU-MP-2, as potent and selective BRK inhibitors. XMU-MP-2 exhibited target-specific inhibition of BRK kinase activity and disrupted signaling pathways mediated by this activity, thereby reducing proliferation in BRK-positive breast Cancer cells. In mouse xenograft models, XMU-MP-2 repressed the growth of tumors driven by oncogenic BRK, including BRK-transformed Ba/F3 cells and BRK-positive breast Cancer cells. Notably, XMU-MP-2 cooperated strongly with HER2 inhibitor or ER blockade to block breast Cancer cell proliferation in vitro and in vivo Overall, our findings offer a preclinical proof of concept for therapeutic targeting of the BRK kinase in breast Cancer. Cancer Res; 77(1); 175-86. ©2016 AACR.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-122664
    99.29%, BRK Inhibitor
    BRK