2. Academic Validation
  3. Discovery of a Potent and Selective Fragment-like Inhibitor of Methyllysine Reader Protein Spindlin 1 (SPIN1)

Discovery of a Potent and Selective Fragment-like Inhibitor of Methyllysine Reader Protein Spindlin 1 (SPIN1)

  • J Med Chem. 2019 Oct 24;62(20):8996-9007. doi: 10.1021/acs.jmedchem.9b00522.
Yan Xiong 1,  Holger Greschik 2,  Catrine Johansson 3,  Ludwig Seifert 4,  Johannes Bacher 4,  Kwang-Su Park 1,  Nicolas Babault 1,  Michael Martini 1,  Vincent Fagan 5,  Fengling Li,  Irene Chau,  Thomas Christott 5,  David Dilworth,  Dalia Barsyte-Lovejoy 6,  Masoud Vedadi 7,  Cheryl H Arrowsmith,  Paul Brennan 5,  Oleg Fedorov 5,  Manfred Jung 4 8 9,  Gillian Farnie 5,  Jing Liu 1,  Udo Oppermann 3,  Roland Schüle 2 10 9,  Jian Jin 1
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Urology and Center for Clinical Research , University Freiburg Medical Center , Freiburg 79106 , Germany.
  • 3 Structural Genomics Consortium, Botnar Research Center, NIHR Oxford BRU , University of Oxford , Oxford OX37LD , U.K.
  • 4 Institute of Pharmaceutical Sciences , University of Freiburg , Freiburg 79104 , Germany.
  • 5 Structural Genomics Consortium & Target Discovery Institute , University of Oxford , Oxford OX37DQ and OX37FZ, U.K.
  • 6 Nature Research Center , Akademijos 2 , Vilnius 08412 , Lithuania.
  • 7 Department of Pharmacology and Toxicology , University of Toronto , Toronto , Ontario M5S 1A8 , Canada.
  • 8 German Cancer Research Centre (DKFZ) , Heidelberg 69120 , Germany.
  • 9 German Cancer Consortium (DKTK) , Freiburg 79106 , Germany.
  • 10 BIOSS Centre of Biological Signalling Studies , University of Freiburg , Freiburg 79106 , Germany.
PMID: 31260300 DOI: 10.1021/acs.jmedchem.9b00522
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 nontumorigenic 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.

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