- PROTEIN KINASE MKK4 INHIBITORS FOR PROMOTING LIVER REGENERATION OR REDUCING OR PREVENTING HEPATOCYTE DEATH
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The invention relates to pyrazolo-pyridine compounds which inhibit mitogen-activated protein kinase kinase 4 (MKK4) and in particular, selectively inhibit MKK4 over protein kinases JNK1 and MKK7. The compounds are useful for promoting liver regeneration or reducing or preventing hepatocyte death. They are further useful for treating osteoarthritis or rheumatoid arthritis, or CNS-related diseases.
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Page/Page column 64
(2019/08/26)
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- PROTEIN KINASE INHIBITORS FOR PROMOTING LIVER REGENERATION OR REDUCING OR PREVENTING HEPATOCYTE DEATH
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The invention relates to MKK4 (mitogen-activated protein kinase 4) and their use in promoting liver regeneration or reducing or preventing hepatocyte death. The MKK4 inhibitors selectively inhibit protein kinase MKK4 over protein kinases JNK and MKK7.
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Page/Page column 78
(2018/08/12)
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- Docking-based structural splicing and reassembly strategy to develop novel deazapurine derivatives as potent B-Raf V600E inhibitors
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The mutation of B-Raf V600E is widespread in a variety of human cancers. Its inhibitors vemurafenib and dabrafenib have been launched as drugs for treating unresectable melanoma, demonstrating that B-Raf V600E is an ideal drug target. This study focused on developing novel B-Raf V600E inhibitors as drug leads against various cancers with B-Raf V600E mutation. Using molecular modeling approaches, 200 blockbuster drugs were spliced to generate 283 fragments followed by molecular docking to identify potent fragments. Molecular structures of potential inhibitors of B-Raf V600E were then obtained by fragment reassembly followed by docking to predict the bioactivity of the reassembled molecules. The structures with high predicted bioactivity were synthesized, followed by in vitro study to identify potent B-Raf V600E inhibitors. A highly potent fragment binding to the hinge area of B-Raf V600E was identified via a docking-based structural splicing approach. Using the fragment, 14 novel structures were designed by structural reassembly, two of which were predicted to be as strong as marketed B-Raf V600E inhibitors. Biological evaluation revealed that compound 1m is a potent B-Raf V600E inhibitor with an IC 50 value of 0.05 μmol/L, which was lower than that of vemurafenib (0.13 μmol/L). Moreover, the selectivity of 1m against B-Raf WT was enhanced compared with vemurafenib. In addition, 1m exhibits desirable solubility, bioavailability and metabolic stability in in vitro assays. Thus, a highly potent and selective B-Raf V600E inhibitor was designed via a docking-based structural splicing and reassembly strategy and was validated by medicinal synthesis and biological evaluation.
- Wang, Gui-Min,Wang, Xiang,Zhu, Jian-Ming,Guo, Bin-Bin,Yang, Zhuo,Xu, Zhi-Jian,Li, Bo,Wang, He-Yao,Meng, Ling-Hua,Zhu, Wei-Liang,Ding, Jian
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p. 1059 - 1068
(2017/07/11)
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- Protein kinase inhibitor and its composition and use thereof
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The invention relates to compounds as shown in the general formula (I), pharmaceutical compositions containing the compounds, a method for treating diseases and disease symptoms related to abnormal activity of protein kinase by using the compounds, and medicinal use of the compounds.
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Paragraph 0159-0161
(2017/08/02)
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- KINASE MODULATING COMPOUNDS, COMPOSITIONS CONTAINING THE SAME AND USE THEREOF
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The invention provides a compound represented by formula (I) which may modulate a kinase, and a pharmaceutical composition thereof, as well as the method for preventing or treating a protein kinase mediated disease or condition.
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Page/Page column 26
(2013/06/05)
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- Synthesis of 2,6-difluoro-N-(3-[11C]methoxy-1H-pyrazolo[3,4-b] pyridine-5-yl)-3-(propylsulfonamidio)benzamide as a new potential PET agent for imaging of B-RafV600E in cancers
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The authentic standard 2,6-difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b] pyridine-5-yl)-3-(propylsulfonamidio)benzamide was synthesized from 2,6-difluorobenzoic acid and 3-amino-5-hydroxypyrazole in 9 steps with 1% overall chemical yield. Direct desmethylation
- Wang, Min,Gao, Mingzhang,Miller, Kathy D.,Zheng, Qi-Huang
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p. 1017 - 1021
(2013/03/13)
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- BENZENE SULFONAMIDE THIAZOLE AND OXAZOLE COMPOUNDS
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The present invention provides thiazole sulfonamide and oxazole sulfonamide compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.
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Page/Page column 168
(2011/06/16)
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