A potent and selective inhibitor for the UBLCP1 proteasome phosphatase
作者： Yantao He , Xing Guo , Zhi-Hong Yu , Li Wu , Andrea M. Gunawan
DOI: 10.1016/J.BMC.2015.03.066
关键词:
摘要: Abstract The ubiquitin-like domain-containing C-terminal domain phosphatase 1 (UBLCP1) has been implicated as a negative regulator of the proteasome, key mediator in ubiquitin-dependent protein degradation. Small molecule inhibitors that block UBLCP1 activity would be valuable research tools and potential therapeutics for human diseases caused by cellular accumulation misfold/damaged proteins. We report salicylic acid fragment-based library approach aimed at targeting both active site its adjacent binding pocket enhanced affinity selectivity. Screening focused libraries led to identification first potent selective inhibitor 13. Compound 13 exhibits an IC50 1.0 μM greater than 5-fold selectivity against large panel phosphatases from several distinct families. Importantly, possesses efficacious is capable inhibiting function cells, which turn up-regulates nuclear proteasome activity. These studies set groundwork further developing compound into chemical probes or therapeutic agents phosphatase.
elsevier.com
sci-hub.se 参考文章(55)
Li-Fan Zeng, Ruo-Yu Zhang, Yunpeng Bai, Li Wu, Andrea M. Gunawan, Zhong-Yin Zhang, Hydroxyindole carboxylic acid-based inhibitors for receptor-type protein tyrosine protein phosphatase beta. Antioxidants & Redox Signaling. ,vol. 20, pp. 2130- 2140 ,(2014) , 10.1089/ARS.2013.5463
M F Sanner, Python: a programming language for software integration and development. Journal of Molecular Graphics & Modelling. ,vol. 17, pp. 57- 61 ,(1999)
Nico P. Dantuma, Kristina Lindsten, Rickard Glas, Marianne Jellne, Maria G. Masucci, Short-lived green fluorescent proteins for quantifying ubiquitin/proteasome-dependent proteolysis in living cells Nature Biotechnology. ,vol. 18, pp. 538- 543 ,(2000) , 10.1038/75406
Xue Li, Kenneth A Ohgi, Jie Zhang, Anna Krones, Kevin T Bush, Christopher K Glass, Sanjay K Nigam, Aneel K Aggarwal, Richard Maas, David W Rose, Michael G Rosenfeld, None, Eya protein phosphatase activity regulates Six1–Dach–Eya transcriptional effects in mammalian organogenesis Nature. ,vol. 426, pp. 247- 254 ,(2003) , 10.1038/NATURE02083
Fengxue Zhang, Yong Hu, Ping Huang, Clifford A Toleman, Andrew J Paterson, Jeffrey E Kudlow, None, Proteasome function is regulated by cyclic AMP-dependent protein kinase through phosphorylation of Rpt6. Journal of Biological Chemistry. ,vol. 282, pp. 22460- 22471 ,(2007) , 10.1074/JBC.M702439200
Yan Zhang, Youngjun Kim, Nicolas Genoud, Jianmin Gao, Jeffery W. Kelly, Samuel L. Pfaff, Gordon N. Gill, Jack E. Dixon, Joseph P. Noel, Determinants for Dephosphorylation of the RNA Polymerase II C-Terminal Domain by Scp1 Molecular Cell. ,vol. 24, pp. 759- 770 ,(2006) , 10.1016/J.MOLCEL.2006.10.027
Fred E. Cohen, Jeffery W. Kelly, Therapeutic approaches to protein-misfolding diseases Nature. ,vol. 426, pp. 905- 909 ,(2003) , 10.1038/NATURE02265
Mauro Sarmiento, Li Wu, Yen-Fang Keng, Li Song, Zhaowen Luo, Ziwei Huang, Guo-Zhang Wu, Adam K. Yuan, Zhong-Yin Zhang, Structure-based discovery of small molecule inhibitors targeted to protein tyrosine phosphatase 1B. Journal of Medicinal Chemistry. ,vol. 43, pp. 146- 155 ,(2000) , 10.1021/JM990329Z
Jacques Archambault, Guohua Pan, Grace K Dahmus, Mireille Cartier, Nick Marshall, Sherry Zhang, Michael E Dahmus, Jack Greenblatt, None, FCP1, the RAP74-Interacting Subunit of a Human Protein Phosphatase That Dephosphorylates the Carboxyl-terminal Domain of RNA Polymerase IIO Journal of Biological Chemistry. ,vol. 273, pp. 27593- 27601 ,(1998) , 10.1074/JBC.273.42.27593
Mengmeng Zhang, Eun Jeong Cho, Gayle Burstein, Dionicio Siegel, Yan Zhang, Selective inactivation of a human neuronal silencing phosphatase by a small molecule inhibitor. ACS Chemical Biology. ,vol. 6, pp. 511- 519 ,(2011) , 10.1021/CB100357T