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Front. Pharmacol. | doi: 10.3389/fphar.2018.00173

Identification of a Novel Protein Arginine Methyltransferase 5 Inhibitor in Non-small Cell Lung Cancer by Structure-based Virtual Screening

Qian Qian Wang1, Jia Hui Xu1, Ying Li1, Ju Min Huang1, Ze Bo Jiang1,  Yu Wei Wang1, Liang Liu1*,  Elaine Leung1, 2, 3* and  Xiao Jun Yao1, 4*
  • 1State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, China
  • 2First Affiliated Hospital of Guangzhou Medical University, China
  • 3Taihe Hospital, Hubei University of Medicine, China
  • 4Lanzhou University, China

Protein arginine methyltransferase 5 (PRMT5) is able to regulate gene transcription by catalyzing the symmetrical dimethylation of arginine residue of histone, which plays a key role in tumorigenesis. Many efforts have been taken in discovering small-molecular inhibitors against PRMT5, but very few were reported and most of them were SAM-competitive. EPZ015666 is a recently reported PRMT5 inhibitor with a new binding site, which is different from S-adenosylmethionine (SAM)-binding pocket. This new binding site provides a new clue for the design and discovery of potent and specific PRMT5 inhibitors. In this study, the structure-based virtual screening targeting this site was firstly performed to identify potential PRMT5 inhibitors. Then, the bioactivity of the candidate compound was studied. MTT results showed that compound T1551 decreased cell viability of A549 and H460 non-small cell lung cancer cell lines. By inhibiting the methyltransferase activity of PRMT5, T1551 reduced the global level of H4R3 symmetric dimethylation (H4R3me2s). T1551 also downregulated the expression of oncogene FGFR3 and eIF4E, and disturbed the activation of related PI3K/AKT/mTOR and ERK signaling in A549 cell. Finally, we investigated the conformational spaces and identified collective motions important for description of T1551/PRMT5 complex by using molecular dynamics simulation and normal mode analysis methods. This study provides a novel non-SAM-competitive hit compound for developing small molecules targeting PRMT5 in non-small cell lung cancer.

Keywords: Protein arginine methyltransferase 5, Non-small cell lung cancer, T1551, Virtual Screening, Molecular dynamic simulation

Received: 31 Oct 2017; Accepted: 15 Feb 2018.

Edited by:

Adriano D. Andricopulo, São Carlos Institute of Physics, University of São Paulo, Brazil

Reviewed by:

Matthew Brook, University of Edinburgh, United Kingdom
Chiara B. Platania, Università degli Studi di Catania, Italy  

Copyright: © 2018 Wang, Xu, Li, Huang, Jiang, Wang, Liu, Leung and Yao. 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 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:
Prof. Liang Liu, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China, lliu@must.edu.mo
Dr. Elaine Leung, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China, lhleung@must.edu.mo
Prof. Xiao Jun Yao, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China, xjyao@must.edu.mo