Developing Spindlin1 small-molecule inhibitors by using protein microarrays

Nature Chemical Biology
Narkhyun BaeMark T Bedford

Abstract

The discovery of inhibitors of methyl- and acetyl-binding domains has provided evidence for the 'druggability' of epigenetic effector molecules. The small-molecule probe UNC1215 prevents methyl-dependent protein-protein interactions by engaging the aromatic cage of MBT domains and, with lower affinity, Tudor domains. Using a library of tagged UNC1215 analogs, we screened a protein-domain microarray of human methyllysine effector molecules to rapidly detect compounds with new binding profiles with either increased or decreased specificity. Using this approach, we identified a compound (EML405) that acquired a novel interaction with the Tudor-domain-containing protein Spindlin1 (SPIN1). Structural studies facilitated the rational synthesis of SPIN1 inhibitors with increased selectivity (EML631-633), which engage SPIN1 in cells, block its ability to 'read' H3K4me3 marks and inhibit its transcriptional-coactivator activity. Protein microarrays can thus be used as a platform to 'target-hop' and identify small molecules that bind and compete with domain-motif interactions.

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Citations

Oct 25, 2017·The Journal of Biological Chemistry·Narkhyun BaeMark T Bedford
Aug 16, 2017·Proceedings of the National Academy of Sciences of the United States of America·Shuai ZhaoHaitao Li
Jun 30, 2019·ChemMedChem·Chakravarthi SimhadriFraser Hof
Oct 5, 2019·Nature Structural & Molecular Biology·Cheryl H Arrowsmith, Matthieu Schapira
Mar 8, 2019·Nature Medicine·Helai P MohammadCaretha L Creasy
May 20, 2019·Cellular and Molecular Life Sciences : CMLS·David Dilworth, Dalia Barsyte-Lovejoy
Jan 11, 2020·Future Medicinal Chemistry·Jarod M Waybright, Lindsey I James
Dec 2, 2020·Proceedings of the National Academy of Sciences of the United States of America·Xingyu LiuMichael P Washburn
Aug 27, 2019·Methods : a Companion to Methods in Enzymology·Jianji ChenMark T Bedford
Feb 27, 2021·Biochemistry·Xiaoyu ZhangBenjamin F Cravatt
Apr 25, 2018·Bioorganic & Medicinal Chemistry Letters·Anup K UpadhyayChaohong Sun
Apr 15, 2021·Current Opinion in Chemical Biology·Isabelle A EngelbergStephen V Frye
Jun 3, 2021·International Journal of Molecular Sciences·Chiara LuiseWolfgang Sippl
Sep 25, 2019·Journal of Medicinal Chemistry·Vincent FaganUdo Oppermann

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