title: Mad2 Inhibitor-1 (M2I-1): A Small Molecule Protein-Protein Interaction Inhibitor Targeting the Mitotic Spindle Assembly Checkpoint.
abstract: The genetic integrity of each organism depends on the faithful segregation of its genome during mitosis. To meet this challenge, a cellular surveillance mechanism, termed the spindle assembly checkpoint (SAC), evolved that monitors the correct attachment of chromosomes and blocks progression through mitosis if corrections are needed. While the central role of the SAC for genome integrity is well established, its functional dissection has been hampered by the limited availability of appropriate small molecule inhibitors. Using a fluorescence polarization-based screen, we identify Mad2 inhibitor-1 (M2I-1), the first small molecule inhibitor targeting the binding of Mad2 to Cdc20, an essential protein-protein interaction (PPI) within the SAC. Based on computational and biochemical analyses, we propose that M2I-1 disturbs conformational dynamics of Mad2 critical for complex formation with Cdc20. Cellular studies revealed that M2I-1 weakens the SAC response, indicating that the compound might be active in cells. Thus, our study identifies the SAC specific complex formation between Mad2 and Cdc20 as a protein-protein interaction that can be targeted by small molecules.
authors.affiliation: †Department of Biology and Konstanz Research School Chemical Biology (KoRS-CB), University of Konstanz, Universitätsstr. 10, 78462 Konstanz, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Kastl
authors.affiliation: ‡Department of Chemistry and Konstanz Research School Chemical-Biology (KoRS-CB), University of Konstanz, Universitätsstr. 10, 78462 Konstanz, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Braun
authors.affiliation: ‡Department of Chemistry and Konstanz Research School Chemical-Biology (KoRS-CB), University of Konstanz, Universitätsstr. 10, 78462 Konstanz, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Prestel
authors.affiliation: ‡Department of Chemistry and Konstanz Research School Chemical-Biology (KoRS-CB), University of Konstanz, Universitätsstr. 10, 78462 Konstanz, Germany.|§Institute of Chemistry, University of Potsdam, Karl-Liebknecht-Str. 24-25, 14476, Potsdam, Germany.
authors.forename: Heiko M
authors.initials: HM
authors.lastname: Möller
authors.affiliation: ‡Department of Chemistry and Konstanz Research School Chemical-Biology (KoRS-CB), University of Konstanz, Universitätsstr. 10, 78462 Konstanz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Huhn
authors.affiliation: †Department of Biology and Konstanz Research School Chemical Biology (KoRS-CB), University of Konstanz, Universitätsstr. 10, 78462 Konstanz, Germany.
authors.forename: Thomas U
authors.initials: TU
authors.lastname: Mayer
mesh_terms: D064199:Cdc20 Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D064246:Mad2 Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects; D062105:Molecular Docking Simulation; D060066:Protein Interaction Maps / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism
chemical_list: D064199:Cdc20 Proteins; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D054852:Small Molecule Libraries