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

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1083-1106
Number of pages24
JournalEuropean Journal of Medicinal Chemistry
Volume126
DOIs
StatePublished - Jan 27 2017
Externally publishedYes

Fingerprint

Cells
Derivatives
Inhibitory Concentration 50
Neoplasms
Oncology
Scaffolds
Body Weight Changes
Toxicity
Tumors
Salts
Cell Cycle Checkpoints
Apoptosis
Cell Proliferation
imidazo(1,2-a)pyridine
In Vitro Techniques
Growth
Therapeutics

Keywords

  • Antitumor activity
  • Imidazo[1,2-a]pyridine
  • Nek2 inhibitors
  • Selectivity

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

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

In: European Journal of Medicinal Chemistry, Vol. 126, 27.01.2017, p. 1083-1106.

Research output: Contribution to journalArticle

Xi, Jian Bei ; Fang, Yan Fen ; Frett, Brendan ; Zhu, Meng Li ; Zhu, Tong ; Kong, Yan Nan ; Guan, Feng Jie ; Zhao, Yun ; Zhang, Xiong Wen ; Li, Hong Yu ; Ma, Ming Liang ; Hu, Wenhao. / 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. In: European Journal of Medicinal Chemistry. 2017 ; Vol. 126. pp. 1083-1106.
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AU - Zhu, Tong

AU - Kong, Yan Nan

AU - Guan, Feng Jie

AU - Zhao, Yun

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AU - Li, Hong Yu

AU - Ma, Ming Liang

AU - Hu, Wenhao

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