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A Chemical Probe For Tudor Domain Protein Spindlin1 to Investigate Chromatin Functions

preprint
revised on 30.05.2019 and posted on 30.05.2019 by Vincent Fagan, Catrine Johansson, Carina Gileadi, Octovia P. Monteiro, James E. Dunford, Reshma Nibhani, Martin Philpott, Jessica Malzahn, Graham Wells, Ruth Farham, Adam Cribbs, Nadia Halidi, Fengling Li, Irene Chau, Holger Greschik, Srikannathasan Velupillai, Abdellalh Allali- Hassani, James Bennett, Thomas Christott, Charline Giroud, Andrew M Lewis, Kilian Huber, Nick Athanasou, Chas Bountra, Manfred Jung, Roland Schüle, Masoud Vedadi, Cheryl Arrowsmith, Yan Xiong, Jian Jin, Oleg Fedorov, Gillian Farnie, Paul Brennan, Udo Oppermann
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 co-activator. 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 roll in cancer related inflammation and/or cancer metastasis.

Funding

Cancer Research UK C41580/A23900

Oxford NIHR Biomedical Research Centre, Myeloma UK and Arthritis Research UK (program grant 20522)

The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck KGaA Darmstadt Germany, MSD, Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation-FAPESP, Takeda, and Wellcome [106169/ZZ14/Z].

The People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA grant agreement n° [609305].

History

Email Address of Submitting Author

paul.brennan@sgc.ox.ac.uk

Institution

University of Oxford

Country

United Kingdom

ORCID For Submitting Author

0000-0002-8950-7646

Declaration of Conflict of Interest

The authors declare no conflict of interest

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