Design,synthesis, and biological evaluation of new B-RafV600E kinase inhibitors |
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Authors: | Peng-Fei Wang Yong-Jiao Zhang Dong Wang Hui-Min Hu Zhong-Chang Wang Chen Xu Han-Yue Qiu Hai-Liang Zhu |
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Institution: | 1. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People’s Republic of China;2. State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, People’s Republic of China |
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Abstract: | The association of deregulated signal pathways with various diseases has long been a research hotspot. One of the most important signal pathways, the MAPK (mitogen-activated protein kinase) signal pathway, plays a vital role in transducing extracellular signals into vital intracellular mechanisms. While mutations on its key component Raf kinase lead to sever diseases, targeted inhibition has thereby become an attractive therapeutic strategy. Several drugs have been approved for the treatment of Raf relevant diseases, yet more candidates are ever needed as the known drugs have confronted resistance and side effects. In the present study, we primarily investigated the binding modes of type I/II and type II inhibitors with B-Raf kinase. Based on the current knowledge, these ligands were fragmented and recombined to provide new interesting insights. Afterwards, a series of derivatives has been synthesized after the validation of hit compound. In addition, in vitro assays were carried out to profile the pharmacological properties of all the entities. Of all the compounds, compound 5h showed the best profile and may be used in the future study. |
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Keywords: | B-Raf Molecular dynamics Docking Kinase inhibitor Drug design |
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