Structure-based design and synthesis of imidazo[1,2-a]pyridine derivatives as novel and potent Nek2 inhibitors with in vitro and in vivo antitumor activities

Jian-Bei Xi; Yan-Fen Fang; Brendan Frett; Meng-Li Zhu; Tong Zhu; Yan-Nan Kong; Feng-Jie Guan; Yun Zhao; Xiong-Wen Zhang; Hong-Yu Li; Ming-Liang Ma; Wenhao Hu

doi:10.1016/j.ejmech.2016.12.026

Structure-based design and synthesis of imidazo[1,2-a]pyridine derivatives as novel and potent Nek2 inhibitors with in vitro and in vivo antitumor activities

Eur J Med Chem. 2017 Jan 27:126:1083-1106. doi: 10.1016/j.ejmech.2016.12.026. Epub 2016 Dec 12.

Authors

Jian-Bei Xi¹, Yan-Fen Fang¹, Brendan Frett², Meng-Li Zhu¹, Tong Zhu¹, Yan-Nan Kong¹, Feng-Jie Guan¹, Yun Zhao¹, Xiong-Wen Zhang³, Hong-Yu Li⁴, Ming-Liang Ma⁵, Wenhao Hu⁶

Affiliations

¹ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
² Department of Pharmaceutical Science, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
³ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China. Electronic address: xwzhang@sat.ecnu.edu.cn.
⁴ Department of Pharmaceutical Science, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. Electronic address: HLi2@uams.ed.
⁵ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China. Electronic address: mlma@brain.ecnu.edu.cn.
⁶ Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China. Electronic address: whu@chem.ecnu.edu.cn.

PMID: 28039836
DOI: 10.1016/j.ejmech.2016.12.026

Abstract

We present herein the discovery and development of novel and potent Nek2 inhibitors with distinctive in vitro and in vivo antitumor activity based on an imidazo[1,2-a]pyridine scaffold. Our studies identified a nonlinear SAR for activity against both Nek2 and cancer cells. Bioisostere and structure-based design techniques were employed to identify compounds 42c (MBM-17, IC₅₀ = 3.0 nM) and 42g (MBM-55, IC₅₀ = 1.0 nM), which displayed low nanomolar activity and excellent selectivity for Nek2. Both compounds effectively inhibited the proliferation of cancer cells by inducing cell cycle arrest and apoptosis. Importantly, the salts form of these two compounds (MBM-17S and MBM-55S) significantly suppressed tumor growth in vivo without apparent toxicity based on appearance and changes in body weight. In summary, MBM-17 and MBM-55 displayed the potential for substantial therapeutic application in cancer treatment.

Keywords: Antitumor activity; Imidazo[1,2-a]pyridine; Nek2 inhibitors; Selectivity.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Chemistry Techniques, Synthetic
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Female
G2 Phase Cell Cycle Checkpoints / drug effects
Humans
M Phase Cell Cycle Checkpoints / drug effects
Male
Mice
Molecular Docking Simulation
NIMA-Related Kinases / antagonists & inhibitors*
NIMA-Related Kinases / chemistry
NIMA-Related Kinases / metabolism
Nitrazepam / chemistry*
Polyploidy
Protein Conformation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology
Pyridines / chemical synthesis*
Pyridines / chemistry
Pyridines / pharmacokinetics
Pyridines / pharmacology*
Rats
Structure-Activity Relationship
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyridines
Nitrazepam
NEK2 protein, human
NIMA-Related Kinases