2. Academic Validation
  3. Development of the First Covalent Monopolar Spindle Kinase 1 (MPS1/TTK) Inhibitor

Development of the First Covalent Monopolar Spindle Kinase 1 (MPS1/TTK) Inhibitor

  • J Med Chem. 2022 Feb 24;65(4):3173-3192. doi: 10.1021/acs.jmedchem.1c01165.
Ricardo A M Serafim 1 2 3,  André da Silva Santiago 2 3,  Martin P Schwalm 4 5,  Zexi Hu 6 7,  Caio V Dos Reis 2 3,  Jessica E Takarada 2 3,  Priscila Mezzomo 2 3,  Katlin B Massirer 2 3,  Mark Kudolo 1,  Stefan Gerstenecker 1,  Apirat Chaikuad 4 5,  Lars Zender 6 7 8,  Stefan Knapp 4 5 9,  Stefan Laufer 1 7 10,  Rafael M Couñago 2 3,  Matthias Gehringer 1 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
  • 2 Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas, SP 13083-875, Brazil.
  • 3 Structural Genomics Consortium, Departamento de Genética e Evolução, Instituto de Biologia, UNICAMP, Campinas, SP 13083-886, Brazil.
  • 4 Structural Genomics Consortium, Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany.
  • 5 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany.
  • 6 Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen, 72076 Tübingen, Germany.
  • 7 Cluster of Excellence iFIT (EXC 2180) 'Image-Guided & Functionally Instructed Tumor Therapies', University of Tübingen, 72076 Tübingen, Germany.
  • 8 German Consortium for Translational Cancer Research (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), 72076 Tübingen, Germany.
  • 9 Frankfurt Cancer Institute (FCI) and German Translational Cancer Network (DKTK) Site Frankfurt/Mainz, 60596 Frankfurt am Main, Germany.
  • 10 Tübingen Center for Academic Drug Discovery, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
PMID: 35167750 DOI: 10.1021/acs.jmedchem.1c01165
Abstract

Monopolar spindle kinase 1 (Mps1/TTK) is a key element of the mitotic checkpoint and clinically evaluated as a target in the treatment of aggressive tumors such as triple-negative breast Cancer. While long drug-target residence times have been suggested to be beneficial in the context of therapeutic Mps1 inhibition, no irreversible inhibitors have been reported. Here we present the design and characterization of the first irreversible covalent Mps1 Inhibitor, RMS-07, targeting a poorly conserved cysteine in the kinase's hinge region. RMS-07 shows potent Mps1 inhibitory activity and selectivity against all protein kinases with an equivalent cysteine but also in a broader kinase panel. We demonstrate potent cellular target engagement and pronounced activity against various Cancer cell lines. The covalent binding mode was validated by mass spectrometry and an X-ray crystal structure. This proof of Mps1 covalent ligandability may open new avenues for the design of MPS1-specific chemical probes or drugs.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-144308
    MPS1/TTK Inhibitor