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Molecules 2018, 23(3), 565;

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

1,2,3,* and 1,2,3,*
Henan University Joint National Laboratory for Antibody Drug Engineering, Kaifeng 475004, China
Henan University Medical bioinformatics institute, Kaifeng 475004, China
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)
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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)

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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.

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