Structure-based design and SAR development of novel selective polo-like kinase 1 inhibitors having the tetrahydropteridin scaffold

Eur J Med Chem. 2019 Dec 15:184:111769. doi: 10.1016/j.ejmech.2019.111769.

Xiao Lv ¹, Xiaoxiao Yang ¹, Mei-Miao Zhan ², Peichang Cao ¹, Shihong Zheng ¹, Ruijun Peng ², Jihong Han ¹, Zhouling Xie ³, Zhengchao Tu ⁴, Chenzhong Liao ⁵

Affiliations

1 Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei, 230009, China; School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China.
2 School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China.
3 Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei, 230009, China; School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China. Electronic address: zhoulingxie@hfut.edu.cn.
4 International Cooperative Laboratory of Traditional Chinese Medicine Modernization, Innovative Drug Development of Chinese Ministry of Education, College of Pharmacy, Jinan University, Guangzhou, 510632, China; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. Electronic address: tu_zhengchao@gibh.ac.cn.
5 Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei, 230009, China; School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China. Electronic address: czliao@hfut.edu.cn.

PMID: 31629162 DOI: 10.1016/j.ejmech.2019.111769

Abstract

Polo-like kinase 1 (PLK1) is a validated target for the treatment of Cancer. In this report, by analyzing amino acid residue differences among the ATP-binding pockets of PLK1, PLK2 and PLK3, novel selective PLK1 inhibitors were designed based on BI 2536 and BI 6727, two PLK1 inhibitors in clinical studies for Cancer treatments. The PLK1 inhibitors reported herein have more potent inhibition against PLK1 and better isoform selectivity in the Plk family than these two lead compounds. In addition, by introducing a hydroxyl group, our compounds have significantly improved solubility and may target specific polar residues Arg57, Glu69 and Arg134 of PLK1. Moreover, most of our compounds exhibited antitumor activities in the nanomolar range against several Cancer cell lines in the MTT assay. Through this structure-based design strategy and SAR study, a few promising selective PLK1 inhibitors having the tetrahydropteridin scaffold, for example, L34, were identified and could be for further Anticancer research.

Keywords

Anticancer; Isoform selectivity; Plk1 inhibitor; Structure activity relationship; Structure-based drug design.

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