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LPE-1, an Orally Active Pyrimidine Derivative, Inhibits Growth and Mobility of Human Esophageal Cancers by Targeting LSD1

LPE-1, an Orally Active Pyrimidine Derivative, Inhibits Growth and Mobility of Human Esophageal Cancers by Targeting LSD1

Bo Wang, Bing Zhao, Lu-Ping Pang, Yuan-Di Zhao, Qian Guo, Jun-Wei Wang, Yi-Chao Zheng, Xin-Hui Zhang, Ying Liu, Guang-Yao Liu, Wen-Ge Guo, Chao Wang, Zhong-Hua Li, Xue-Jing Mao, Bin Yu, Li-Ying Ma, Hong-Min Liu

Pharmacol Res. 2017 Aug;122:66-77.

PMID: 28571892

Abstract:

Histone lysine specific demethylase 1 (LSD1) plays an important role in epigenetic modifications, and aberrant expression of LSD1 predicts tumor progression and poor prognosis in human esophageal cancers. In this study, a series of LSD1 inhibitors were synthesized and proved to be highly potent against human esophageal squamous cell carcinoma (ESCC). Our data showed that these LSD1 inhibitors selectively suppressed the viability of esophageal cancer cell line (EC-109) bearing overexpressed LSD1. Among these, compound LPE-1 (LSD1 IC50=0.336±0.003μM) significantly suppressed proliferation, induced apoptosis, arrested cell cycle of EC109 cells at G2/M phase, and caused changes of the associated protein markers correspondingly. We also found that compound LPE-1 potently inhibited the migration and invasion of EC-109 cells. Docking studies showed that the cyano group formed hydrogen bonds with Val811 and Thr810. Additionally, the thiophene moiety formed arene-H interaction with Trp761 residue. In vivo studies showed that compound LPE-1 inhibited tumor growth of xenograft models bearing EC-109 without obvious toxicity. Collectively, our findings indicate that LSD1 may be a potential therapeutic target in ESCC, and compound LPE-1 could serve as a lead compound for further development for anti-ESCC drug discovery.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42416057	LSD1 Active human			Price

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