| Literature DB >> 31550156 |
Vincent Fagan1,2, Catrine Johansson1,3, Carina Gileadi1,3, Octovia Monteiro1,2, James E Dunford3, Reshma Nibhani3, Martin Philpott3, Jessica Malzahn3, Graham Wells3, Ruth Faram3, Adam P Cribbs3, Nadia Halidi1,3, Fengling Li4, Irene Chau4, Holger Greschik5, Srikannathasan Velupillai1, Abdellah Allali-Hassani4, James Bennett1,2, Thomas Christott1,2, Charline Giroud1,2, Andrew M Lewis1,2, Kilian V M Huber1,2, Nick Athanasou3, Chas Bountra1, Manfred Jung6,7, Roland Schüle5, Masoud Vedadi4, Cheryl Arrowsmith4, Yan Xiong8, Jian Jin8, Oleg Fedorov1,2, Gillian Farnie1,3, Paul E Brennan1,2,9, Udo Oppermann1,3,6.
Abstract
Modifications of histone tails, including lysine/arginine methylation, provide the basis of a "chromatin or histone code". Proteins that contain "reader" domains can bind to these modifications and form specific effector complexes, which ultimately mediate chromatin function. The spindlin1 (SPIN1) protein contains three Tudor methyllysine/arginine reader domains and was identified as a putative oncogene and transcriptional coactivator. Here we report a SPIN1 chemical probe inhibitor with low nanomolar in vitro activity, exquisite selectivity on a panel of methyl reader and writer proteins, and with submicromolar cellular activity. X-ray crystallography showed that this Tudor domain chemical probe simultaneously engages Tudor domains 1 and 2 via a bidentate binding mode. Small molecule inhibition and siRNA knockdown of SPIN1, as well as chemoproteomic studies, identified genes which are transcriptionally regulated by SPIN1 in squamous cell carcinoma and suggest that SPIN1 may have a role in cancer related inflammation and/or cancer metastasis.Entities:
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Year: 2019 PMID： 31550156 DOI： 10.1021/acs.jmedchem.9b00562
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446