Next Article in Journal
A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing
Previous Article in Journal
Synergistic Effects of Salvianolic Acid B and Puerarin on Cerebral Ischemia Reperfusion Injury
Article Menu
Issue 3 (March) cover image

Export Article

Open AccessArticle
Molecules 2018, 23(3), 565; https://doi.org/10.3390/molecules23030565

New Drug Candidate Targeting the 4A1 Orphan Nuclear Receptor for Medullary Thyroid Cancer Therapy

1,2,3,†
,
3,†
,
3,†
,
3
,
1,2,3
,
3
,
1,2,3
,
1,2,3
,
1,2,3,* and 1,2,3,*
1
Henan University Joint National Laboratory for Antibody Drug Engineering, Kaifeng 475004, China
2
Henan University Medical bioinformatics institute, Kaifeng 475004, China
3
Henan University School of Basic Medical Sciences, Kaifeng 475004, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 21 December 2017 / Revised: 15 February 2018 / Accepted: 28 February 2018 / Published: 2 March 2018
(This article belongs to the Section Medicinal Chemistry)
Full-Text   |   PDF [15130 KB, uploaded 2 March 2018]   |  

Abstract

Medullary thyroid cancer (MTC) is a relatively rare thyroid cancer responsible for a substantial fraction of thyroid cancer mortality. More effective therapeutic drugs with low toxicity for MTC are urgently needed. Orphan nuclear receptor 4A1 (NR4A1) plays a pivotal role in regulating the proliferation and apoptosis of a variety of tumor cells. Based on the NR4A1 protein structure, 2-imino-6-methoxy-2H-chromene-3-carbothioamide (IMCA) was identified from the Specs compounds database using the protein structure-guided virtual screening approach. Computationally-based molecular modeling studies suggested that IMCA has a high affinity for the ligand binding pocket of NR4A1. MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide] and apoptosis assays demonstrated that IMCA resulted in significant thyroid cancer cell death. Immunofluorescence assays showed that IMCA induced NR4A1 translocation from the nucleus to the cytoplasm in thyroid cancer cell lines, which may be involved in the cell apoptotic process. In this study, the quantitative polymerase chain reaction results showed that the IMCA-induced upregulation of sestrin1 and sestrin2 was dose-dependent in thyroid cancer cell lines. Western blot showed that IMCA increased phosphorylation of adenosine 5′-monophosphate-activated protein kinase (AMPK) and decreased phosphorylation of ribosomal protein S6 kinase (p70S6K), which is the key enzyme in the mammalian target of rapamycin (mTOR) pathway. The experimental results suggest that IMCA is a drug candidate for MTC therapy and may work by increasing the nuclear export of NR4A1 to the cytoplasm and the tumor protein 53 (p53)-sestrins-AMPK-mTOR signaling pathway. View Full-Text
Keywords: orphan nuclear receptor 4A1 (NR4A1); thyroid cancer; 2-imino-6-methoxy-2H-chromene-3-carbothioamide (IMCA) orphan nuclear receptor 4A1 (NR4A1); thyroid cancer; 2-imino-6-methoxy-2H-chromene-3-carbothioamide (IMCA)
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material

SciFeed

Share & Cite This Article

MDPI and ACS Style

Zhang, L.; Liu, W.; Wang, Q.; Li, Q.; Wang, H.; Wang, J.; Teng, T.; Chen, M.; Ji, A.; Li, Y. New Drug Candidate Targeting the 4A1 Orphan Nuclear Receptor for Medullary Thyroid Cancer Therapy. Molecules 2018, 23, 565.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top