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Discovery of a potent and selective fragment-like inhibitor of methyllysine reader protein spindlin 1 (SPIN1)

DOI: 10.1021/acs.jmedchem.9b00522 DOI Help

Authors: Yan Xiong (Icahn School of Medicine at Mount Sinai) , Holger Greschik (University Freiburg Medical Center) , Catrine Johansson (Structural Genomics Consortium Oxford, University of Oxford) , Ludwig Seifert (University of Freiburg) , Johannes Bacher (University of Freiburg) , Kwang-su Park (Icahn School of Medicine at Mount Sinai) , Nicolas Babault (Icahn School of Medicine at Mount Sinai) , Michael L. Martini (Icahn School of Medicine at Mount Sinai) , Vincent Fagan (Structural Genomics Consortium & Target Discovery Institute, University of Oxford) , Fengling Li (Structural Genomics Consortium, University of Toronto) , Irene Chau (Structural Genomics Consortium, University of Toronto) , Thomas Christott (Structural Genomics Consortium & Target Discovery Institute, University of Oxford) , David Dilworth (Structural Genomics Consortium, University of Toronto) , Dalia Barsyte-lovejoy (Structural Genomics Consortium, University of Toronto; Nature Research Center, Vilnius) , Masoud Vedadi (Structural Genomics Consortium, University of Toronto) , Cheryl H. Arrowsmith (Structural Genomics Consortium, University of Toronto) , Paul E. Brennan (Structural Genomics Consortium & Target Discovery Institute, University of Oxford) , Oleg Fedorov (Structural Genomics Consortium & Target Discovery Institute) , Manfred Jung (University of Freiburg; German Cancer Research Centre (DKFZ); German Cancer Consortium (DKTK)) , Gillian Farnie (Structural Genomics Consortium & Target Discovery Institute, University of Oxford) , Jing Liu (Icahn School of Medicine at Mount Sinai) , Udo C. T. Oppermann (Structural Genomics Consortium, University of Oxford) , Roland Schüle (University Freiburg Medical Center; German Cancer Consortium (DKTK)) , Jian Jin (Icahn School of Medicine at Mount Sinai)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: July 2019

Abstract: By screening an epigenetic compound library, we identified that UNC0638, a highly potent inhibitor of the histone methyltransferases G9a and GLP, was a weak inhibitor of SPIN1 (Spindlin 1), a methyllysine reader protein. Our optimization of this weak hit resulted in the discovery of a potent, selective and cell-active SPIN1 inhibitor, compound 3 (MS31). Compound 3 potently inhibited binding of trimethyllysine-containing peptides to SPIN1, displayed high binding affinity, was highly selective for SPIN1 over other epigenetic readers and writers, directly engaged SPIN1 in cells, and was not toxic to non-tumorigenic cells. The crystal structure of the SPIN1–compound 3 complex indicated that it selectively binds Tudor domain II of SPIN1. We also designed a structurally similar but inactive compound 4 (MS31N) as a negative control. Our results have demonstrated for the first time that potent, selective and cell-active fragment-like inhibitors can be generated by targeting a single Tudor domain.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography