NDLI: Discovery of a small molecule targeting ULK1-modulated cell death of triple negative breast cancer <i>in vitro</i> and <i>in vivo</i>

Content Provider	Royal Society of Chemistry (RSC)
Author	Zhang, Jin Liu, Bo Zhang, Shouyue Zhang, Lan Fu, Leilei Ouyang, Liang Zheng, Yaxin Zhao, Yuqian Yang, Shengyong He, Gu
Copyright Year	2017
Abstract	UNC-51-like kinase 1 (ULK1) is well-known to initiate autophagy, and the downregulation of ULK1 has been found in most breast cancer tissues. Thus, the activation of ULK1-modulated autophagy could be a promising strategy for breast cancer therapy. In this study, we found that ULK1 was remarkably downregulated in breast cancer tissue samples by The Cancer Genome Atlas (TCGA) analysis and tissue microarray (TMA) analysis, especially in triple negative breast cancer (TNBC). To design a ULK1 agonist, we integrated in silico screening and chemical synthesis to acquire a series of small molecule candidates. After rounds of kinase and anti-proliferative activity screening, we discovered the small molecule, LYN-1604, to be the best candidate for a ULK1 agonist. Additionally, we identified that three amino acid residues (LYS50, LEU53, and TYR89) were key to the activation site of LYN-1604 and ULK1 by site-directed mutagenesis and biochemical assays. Subsequently, we demonstrated that LYN-1604 could induce cell death, associated with autophagy by the ULK complex (ULK1-mATG13-FIP200-ATG101) in MDA-MB-231 cells. To further explore LYN-1604-induced autophagic mechanisms, we found some potential ULK1 interactors, such as ATF3, RAD21, and caspase3, by performing comparative microarray analysis. Intriguingly, we found that LYN-1604 induced cell death involved in ATF3, RAD21, and caspase3, accompanied by autophagy and apoptosis. Moreover, we demonstrated that LYN-1604 has potential for good therapeutic effects on TNBC by targeting ULK1-modulated cell death in vivo; thus making this ULK1 agonist a novel potential small-molecule drug candidate for future TNBC therapy.
Starting Page	2687
Ending Page	2701
Page Count	15
File Format	HTM / HTML PDF
ISSN	20416520
Volume Number	8
Issue Number	4
Journal	Chemical Science
DOI	10.1039/c6sc05368h
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Subscribed
Subject Keyword	LYN Agonist TMA Tissue microarray Breast cancer Autophagy The Cancer Genome Atlas Triple-negative breast cancer DNA microarray Kinase Carboxylic acid Ulk Site-directed mutagenesis RAD21 ULK1 List of breast cancer cell lines TNBC ATF3 Trimethoxyamphetamine Apoptosis
Content Type	Text
Resource Type	Article
Subject	Chemistry

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