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
| Autor: | Hong-yu Li, Yan Nan Kong, Meng Li Zhu, Jian Bei Xi, Feng Jie Guan, Yanfen Fang, Mingliang Ma, Brendan Frett, Xiong Wen Zhang, Wenhao Hu, Yun Zhao, Tong Zhu |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Cell cycle checkpoint Protein Conformation Pyridines Antineoplastic Agents Apoptosis Chemistry Techniques Synthetic Polyploidy 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship 0302 clinical medicine In vivo Cell Line Tumor Drug Discovery Pyridine Animals Humans NIMA-Related Kinases Nitrazepam Protein Kinase Inhibitors Cell Proliferation Pharmacology Dose-Response Relationship Drug Chemistry Organic Chemistry General Medicine Xenograft Model Antitumor Assays In vitro Rats G2 Phase Cell Cycle Checkpoints Molecular Docking Simulation 030104 developmental biology Biochemistry 030220 oncology & carcinogenesis Drug Design Toxicity Cancer cell M Phase Cell Cycle Checkpoints Female Bioisostere Drug Screening Assays Antitumor |
| Zdroj: | European journal of medicinal chemistry. 126 |
| ISSN: | 1768-3254 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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