A novel pyrrole-imidazole polyamide targets Aurora kinase A and suppresses tumor growth in vivo

Meiqing Li; Danyi Lu; Yulian Cheng; Chunlei Wu; Jianchao Zhang; Wenli Shi; Zhihao Ding; Yanyan Li; Binghua Cheng; Xian Lin; Ximing Shao; Hongchang Li; Lijing Fang; Ke Liu; Wu Su

doi:10.1016/j.bbrc.2021.07.077

A novel pyrrole-imidazole polyamide targets Aurora kinase A and suppresses tumor growth in vivo

Biochem Biophys Res Commun. 2021 Sep 24:571:167-173. doi: 10.1016/j.bbrc.2021.07.077. Epub 2021 Jul 27.

Authors

Meiqing Li¹, Danyi Lu², Yulian Cheng³, Chunlei Wu⁴, Jianchao Zhang⁵, Wenli Shi⁶, Zhihao Ding⁴, Yanyan Li¹, Binghua Cheng¹, Xian Lin⁴, Ximing Shao⁴, Hongchang Li⁴, Lijing Fang⁷, Ke Liu⁸, Wu Su⁹

Affiliations

¹ Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
² Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; Institute of Molecular Rhythm and Metabolism, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
³ Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China; Nano Science and Technology Institute, University of Science and Technology of China, Suzhou, 215123, Jiangsu, China.
⁴ Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
⁵ Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China.
⁶ School of Life and Pharmaceutical Sciences, Hainan University, Haikou, 570228, China; Hainan Key Laboratory for Sustainable Utilization of Tropical Bioresources, College of Tropical Crops, Hainan University, Haikou, 570228, China.
⁷ Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China. Electronic address: lj.fang@siat.ac.cn.
⁸ Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China. Electronic address: ke.liu@siat.ac.cn.
⁹ Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China. Electronic address: wu.su@siat.ac.cn.

PMID: 34330060
DOI: 10.1016/j.bbrc.2021.07.077

Abstract

Aurora kinase A (Aurora A) plays a critical role in regulating cell mitotic progression and has been considered as a promising drug target for cancer therapy. To develop a novel molecule targeting Aurora A with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide (PIP) Hoechst conjugate, PIP-Ht, targeting to a cell-cycle regulated DNA sequence locating at the promoter of human Aurora A gene (AURKA). PIP-Ht potently suppressed AURKA promoter activities, mRNA expression and protein level, induced tumor cell cycle delay and inhibited tumor cell proliferation in vitro. Furthermore, subcutaneous injection of PIP-Ht into mice bearing human cancer xenografts induced significant tumor growth suppression and cell apoptosis. Collectively, PIP-Ht exhibits the potential as an effective therapeutic candidate for the tumor treatment.

Keywords: Aurora A inhibitor; Pyrrole-imidazole polyamide; Tumor cell-cycle.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Aurora Kinase A / antagonists & inhibitors*
Aurora Kinase A / metabolism
Cell Proliferation / drug effects
Cell Survival / drug effects
Drug Screening Assays, Antitumor
Female
Humans
Imidazoles / chemistry
Imidazoles / pharmacology*
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Nylons / chemistry
Nylons / pharmacology*
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrroles / chemistry
Pyrroles / pharmacology*
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Imidazoles
Nylons
Protein Kinase Inhibitors
Pyrroles
imidazole
AURKA protein, human
Aurora Kinase A