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A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function.

Fagan, Vincent and Johansson, Catrine and Gileadi, Carina and Monteiro, Octovia and Dunford, James Edward and Nibhani, Reshma and Philpott, Martin and Malzahn, Jessica and Wells, Graham and Farham, Ruth and Cribbs, Adam and Halidi, Nadia and Li, Fengling and Chau, Irene and Greschik, Holger and Velupillai, Srikannathasan and Allali-Hassani, Abdellah and Bennett, James M and Christott, Thomas and Giroud, Charline and Lewis, Andrew M and Huber, Kilian VM and Athanasou, Nick and Bountra, Chas and Jung, Manfred and Schüle, Roland and Vedadi, Masoud and Arrowsmith, Cheryl H and Xiong, Yan and Jin, Jian and Fedorov, Oleg and Farnie, Gillian and Brennan, Paul E and Oppermann, Udo CT (2019) A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function. Journal of Medicinal Chemistry, 62 (20). pp. 9008-9025. ISSN 0022-2623


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Modifications of histone tails, including lysine/arginine methylation, provide the basis of a 'chromatin or histone code'. Proteins that con-tain 'reader' domains can bind to these modifications and form specific effector complexes, which ultimately mediate chromatin function. The spindlin1 (SPIN1) protein contains three Tudor methyl-lysine/arginine reader domains and was identified as a putative onco-gene and transcriptional co-activator. Here we report a SPIN1 chemi-cal 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, iden-tified genes which are transcriptionally regulated by SPIN1 in squa-mous cell carcinoma and suggest that SPIN1 may have a roll in cancer related inflammation and/or cancer metastasis.

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