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J Med Chem. 2019 Oct 24;62(20):9008-9025. doi: 10.1021/acs.jmedchem.9b00562. Epub 2019 Oct 15.

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

Author information

1
Structural Genomics Consortium, Nuffield Department of Medicine , University of Oxford , OX3 7DQ Oxford , U.K.
2
Target Discovery Institute, Nuffield Department of Medicine , University of Oxford , OX3 7FZ Oxford , U.K.
3
Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, NIHR Bio-medical Research Centre , University of Oxford , Oxford OX3 7LD , U.K.
4
Structural Genomics Consortium , University of Toronto , 101 College Street , Toronto , Ontario M5G 1L7 , Canada.
5
Department of Urology, Center for Clinical Research, Medical Center, Signalling Research Centres BIOSS and CIBSS , University of Freiburg , D-79106 Freiburg , Germany.
6
FRIAS-Freiburg Institute of Advanced Studies , University of Freiburg , 79104 Freiburg , Germany.
7
Institute of Pharmaceutical Sciences , University of Freiburg , Albertstra├če 25 , 79104 Freiburg , Germany.
8
Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences , Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.
9
Alzheimer's Research UK Oxford Drug Discovery Institute, Nuffield Department of Medicine , University of Oxford , OX3 7FZ Oxford , U.K.

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.

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