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Identification of highly potent and selective Cdc25 protein phosphatases inhibitors from miniaturization click-chemistry-based combinatorial libraries.
Jing, Lanlan; Wu, Gaochan; Hao, Xia; Olotu, Fisayo A; Kang, Dongwei; Chen, Chin Ho; Lee, Kuo-Hsiung; Soliman, Mahmoud E S; Liu, Xinyong; Song, Yuning; Zhan, Peng.
Affiliation
  • Jing L; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China.
  • Wu G; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China.
  • Hao X; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China.
  • Olotu FA; Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
  • Kang D; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China.
  • Chen CH; Duke University Medical Center, Box 2926, Surgical Oncology Research Facility, Durham, NC, 27710, USA.
  • Lee KH; Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, United States; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, 40402, Taiwan.
  • Soliman MES; Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa. Electronic address: Soliman@ukzn.ac.za.
  • Liu X; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
  • Song Y; Department of Clinical Pharmacy, Qilu Hospital of Shandong University, 250012, Ji'nan, China. Electronic address: syncat827@163.com.
  • Zhan P; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.
Eur J Med Chem ; 183: 111696, 2019 Dec 01.
Article in En | MEDLINE | ID: mdl-31541869
ABSTRACT
Cell division cycle 25 (Cdc25) protein phosphatases play key roles in the transition between the cell cycle phases and their association with various cancers has been widely proven, which makes them ideal targets for anti-cancer treatment. Though several Cdc25 inhibitors have been developed, most of them displayed low activity and poor subtype selectivity. Therefore, it is extremely important to discover novel small molecule inhibitors with potent activities and significant selectivity for Cdc25 subtypes, not only served as drugs to treat cancer but also to probe its mechanism in transitions. In this study, miniaturized parallel click chemistry synthesis via CuAAC reaction followed by in situ biological screening were used to discover selective Cdc25 inhibitors. The bioassay results showed that compound M2N12 proved to be the most potent Cdc25 inhibitor, which also act as a highly selective Cdc25C inhibitor and was about 9-fold potent than that of NSC 663284. Moreover, M2N12 showed remarkable anti-growth activity against the KB-VIN cell line, equivalent to that of PXL and NSC 663284. An all-atom molecular dynamics (MD) simulation approach was further employed to probe the significant selectivity of M2N12 for Cdc25C relative to its structural homologs Cdc25A and Cdc25B. Overall, above results make M2N12 a promising lead compound for further investigation and structural modification.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cdc25 Phosphatases / Combinatorial Chemistry Techniques / Enzyme Inhibitors / Antineoplastic Agents Type of study: Diagnostic_studies Limits: Humans Language: En Journal: Eur J Med Chem Year: 2019 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cdc25 Phosphatases / Combinatorial Chemistry Techniques / Enzyme Inhibitors / Antineoplastic Agents Type of study: Diagnostic_studies Limits: Humans Language: En Journal: Eur J Med Chem Year: 2019 Document type: Article