2. Academic Validation
  3. Treating Cancer by Spindle Assembly Checkpoint Abrogation: Discovery of Two Clinical Candidates, BAY 1161909 and BAY 1217389, Targeting MPS1 Kinase

Treating Cancer by Spindle Assembly Checkpoint Abrogation: Discovery of Two Clinical Candidates, BAY 1161909 and BAY 1217389, Targeting MPS1 Kinase

  • J Med Chem. 2020 Aug 13;63(15):8025-8042. doi: 10.1021/acs.jmedchem.9b02035.
Volker K Schulze 1,  Ulrich Klar 1,  Dirk Kosemund 1,  Antje M Wengner 1,  Gerhard Siemeister 1,  Detlef Stöckigt 1,  Roland Neuhaus 1,  Philip Lienau 1,  Benjamin Bader 1,  Stefan Prechtl 1,  Simon J Holton 1,  Hans Briem 1,  Tobias Marquardt 2,  Hartmut Schirok 2,  Rolf Jautelat 2,  Rolf Bohlmann 1,  Duy Nguyen 1,  Amaury E Fernández-Montalván 1,  Ulf Bömer 1,  Uwe Eberspaecher 1,  Michael Brüning 1,  Olaf Döhr 1,  Marian Raschke 1,  Bertolt Kreft 1,  Dominik Mumberg 1,  Karl Ziegelbauer 1,  Michael Brands 1,  Franz von Nussbaum 1,  Marcus Koppitz 1
Affiliations

Affiliations

  • 1 Research & Development, Pharmaceuticals, Bayer AG, 13353 Berlin, Germany.
  • 2 Research & Development, Pharmaceuticals, Bayer AG, 42113 Wuppertal, Germany.
PMID: 32338514 DOI: 10.1021/acs.jmedchem.9b02035
Abstract

Inhibition of monopolar spindle 1 (Mps1) kinase represents a novel approach to Cancer treatment: instead of arresting the cell cycle in tumor cells, cells are driven into mitosis irrespective of DNA damage and unattached/misattached chromosomes, resulting in aneuploidy and cell death. Starting points for our optimization efforts with the goal to identify Mps1 inhibitors were two HTS hits from the distinct chemical series "triazolopyridines" and "imidazopyrazines". The major initial issue of the triazolopyridine series was the moderate potency of the HTS hits. The imidazopyrazine series displayed more than 10-fold higher potencies; however, in the early project phase, this series suffered from poor metabolic stability. Here, we outline the evolution of the two hit series to clinical candidates BAY 1161909 and BAY 1217389 and reveal how both clinical candidates bind to the ATP site of Mps1 kinase, while addressing different pockets utilizing different binding interactions, along with their synthesis and preclinical characterization in selected in vivo efficacy models.

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