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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.01379

A novel selective JAK2 inhibitor identified using pharmacological interactions

 Tony E. Lin1,  Wei-Chun Huang-Fu1, 2, 3, Min-Wu Chao1, 2, Tzu-Ying Sung4, Chao-Di Chang1, 2, Yi-Ying Chen1, 2, Jui-Hua Hsieh5, Huang-Ju Tu6, Han-Li Huang7,  Shiow-Lin Pan1, 2, 3, 7 and  Kai-Cheng Hsu1, 2, 7*
  • 1Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taiwan
  • 2Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taiwan
  • 3Tufts Medical Center, United States
  • 4Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Taiwan
  • 5Kelly Government Solutions, United States
  • 6School of Pharmacy, College of Medicine, National Taiwan University, Taiwan
  • 7Taipei Medical University, Taiwan

The JAK2/STAT signaling pathway mediates cytokine receptor signals that are involved in cell growth, survival and homeostasis. JAK2 is a member of the Janus kinase family and aberrant JAK2/STAT is involved with various diseases, making the pathway a therapeutic target. The similarity between the ATP binding site of protein kinases has made development of specific inhibitors difficult. Current JAK2 inhibitors are not selective and produce unwanted side effects. It is thought that increasing selectivity of kinase inhibitors may reduce the side effects seen with current treatment options. Thus, there is a great need for a selective JAK inhibitor. In this study, we identified a JAK2 specific inhibitor. We first identified key pharmacological interactions in the JAK2 binding site by analyzing known JAK2 inhibitors. Then, we performed structure-based virtual screening and filtered compounds based on their pharmacological interactions and identified compound NSC13626 as a potential JAK2 inhibitor. Results of enzymatic assays revealed that against a panel of kinases, compound NSC13626 is a JAK2 inhibitor and has high selectivity towards the JAK isozyme family. In particular, NSC13626 shows high selectivity towards JAK2 and JAK3. Our cellular assays revealed that compound NSC13626 inhibits colorectal cancer cell growth by downregulating phosphorylation of STAT3 and arresting the cell cycle in the S phase. Thus, we believe that compound NSC13626 has potential to be further optimized as a selective JAK2 drug.

Keywords: Selective inhibitor, JAK2, Virtual Screening, Docking, pharmacological

Received: 01 Aug 2018; Accepted: 09 Nov 2018.

Edited by:

Andres Trostchansky, Facultad de Medicina, Universidad de la República, Uruguay

Reviewed by:

Sun Choi, Ewha Womans University, South Korea
Irene Wood, Centro de Investigaciones Biomédicas (CEINBIO), Uruguay  

Copyright: © 2018 Lin, Huang-Fu, Chao, Sung, Chang, Chen, Hsieh, Tu, Huang, Pan and Hsu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Kai-Cheng Hsu, Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, piki@tmu.edu.tw