Publication

Article Metrics

Citations


Online attention

A chemical probe for tudor domain protein spindlin1 to investigate chromatin function

DOI: 10.1021/acs.jmedchem.9b00562 DOI Help

Authors: Vincent Fagan (Structural Genomics Consortium; Target Discovery Institute, University of Oxford) , Catrine Johansson (Structural Genomics Consortium; NIHR Biomedical Research Centre, University of Oxford) , Carina Gileadi (Structural Genomics Consortium; NIHR Biomedical Research Centre, University of Oxford) , Octovia Monteiro (Structural Genomics Consortium; Target Discovery Institute, University of Oxford) , James Edward Dunford (NIHR Biomedical Research Centre, University of Oxford) , Reshma Nibhani (NIHR Biomedical Research Centre, University of Oxford) , Martin Philpott (NIHR Biomedical Research Centre, University of Oxford) , Jessica Malzahn (NIHR Biomedical Research Centre, University of Oxford) , Graham Wells (NIHR Biomedical Research Centre, University of Oxford) , Ruth Farham (NIHR Biomedical Research Centre, University of Oxford) , Adam Cribbs (NIHR Biomedical Research Centre, University of Oxford) , Nadia Halidi (Structural Genomics Consortium, University of Oxford; NIHR Biomedical Research Centre) , Fengling Li (Structural Genomics Consortium, University of Toronto) , Irene Chau (Structural Genomics Consortium, University of Toronto) , Holger Greschik (University Freiburg Medical Center, University of Freiburg) , Srikannathasan Velupillai (Structural Genomic Consortium, Oxford University) , Abdellah Allali-hassani (Structural Genomics Consortium, University of Toronto) , James M. Bennett (Structural Genomics Consortium; Target Discovery Institute, University of Oxford) , Thomas Christott (Structural Genomics Consortium; Target Discovery Institute, University of Oxford) , Charline Giroud (Structural Genomics Consortium; Target Discovery Institute, University of Oxford) , Andrew M. Lewis (Structural Genomics Consortium; Target Discovery Institute, University of Oxford) , Kilian V. M. Huber (Structural Genomics Consortium; Target Discovery Institute, University of Oxford) , Nick Athanasou (NIHR Biomedical Research Centre, University of Oxford) , Chas Bountra , Manfred Jung (University Freiburg Medical Center; FRIAS - Freiburg Institute of Advanced Studies, University of Freiburg) , Roland Schüle (University Freiburg Medical Center, University of Freiburg) , Masoud Vedadi (Structural Genomics Consortium, University of Toronto) , Cheryl H. Arrowsmith (Structural Genomics Consortium, University of Toronto) , Yan Xiong (Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai) , Jian Jin (Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai) , Oleg Fedorov (Structural Genomics Consortium; Target Discovery Institute, University of Oxford) , Gillian Farnie (Structural Genomics Consortium; NIHR Biomedical Research Centre, University of Oxford) , Paul E. Brennan (Structural Genomics Consortium; Target Discovery Institute, University of Oxford; Alzheimer’s Research UK) , Udo C. T. Oppermann (Structural Genomics Consortium; NIHR Biomedical Research Centre, University of Oxford; FRIAS - Freiburg Institute of Advanced Studies, University of Freiburg)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: September 2019
Diamond Proposal Number(s): 10619 , 15433

Abstract: 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.

Subject Areas: Chemistry


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography