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.
Subject(s)
Drug Design , NIMA-Related Kinases/antagonists & inhibitors , Nitrazepam/chemistry , Pyridines/chemical synthesis , Pyridines/pharmacology , 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 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/chemistry , NIMA-Related Kinases/metabolism , Polyploidy , Protein Conformation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacokinetics , Rats , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
The residential areas, science and education areas, urban green lands, commercial districts, urban arterial roads, industrial zones and urban and rural junction districts in seven different functional zones of Luoyang City were taken as research subjects, and sixty-three soil samples were gathered. The concentrations of soil heavy metals were measured and their pollution levels were evaluated by single pollution index and Nemerow complex pollution indices. The ecological risks of soil heavy metals were discussed with Hakanson potential ecological risk index (RI) and their geneses and sources were indicated by the principal component analysis (PCA). The results showed that the average level of all heavy metals exceeded the background values of Henan Province. The pollution degree of single gene index was in the following order:Cd> Zn> Pb> Cu> Ni> Cr. Nemerow complex pollution indices indicated heavy metals had the highest concentration and the heaviest pollution in industrial zones. A single heavy metal potential ecological harm (Eri) showed Cd had the highest risk index. RI was ranked as industrial zones> urban arterial roads> commercial districts> residential areas> science and education areas> urban green lands> rural junction districts. The heavy metal pollution in industrial zones, urban arterial roads and commercial districts reached strong levels, and the pollution in residential areas, science and education areas, urban green lands reached moderate risk levels, but that in rural junction districts belonged to slight risk level. Cu, Zn, Pb and Cd were called anthropogenic factors and came from industrial wastes and transport emissions, but Cr and Ni were explained as natural factors and their contents depended upon the parent materials of soil.
