title: 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.
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.
authors.affiliation: 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.
authors.forename: Jian-Bei
authors.initials: JB
authors.lastname: Xi
authors.affiliation: 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.
authors.forename: Yan-Fen
authors.initials: YF
authors.lastname: Fang
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Frett
authors.affiliation: 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.
authors.forename: Meng-Li
authors.initials: ML
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Yan-Nan
authors.initials: YN
authors.lastname: Kong
authors.affiliation: 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.
authors.forename: Feng-Jie
authors.initials: FJ
authors.lastname: Guan
authors.affiliation: 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.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Xiong-Wen
authors.initials: XW
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Science, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. Electronic address: HLi2@uams.ed.
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Ming-Liang
authors.initials: ML
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Hu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D000072379:NIMA-Related Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D009567:Nitrazepam / Q000737:chemistry*; D011123:Polyploidy; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009567:Nitrazepam; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases
keywords: Antitumor activity; Imidazo[1,2-a]pyridine; Nek2 inhibitors; Selectivity