title: Novel Mps1 Kinase Inhibitors with Potent Antitumor Activity.
abstract: Monopolar spindle 1 (Mps1) has been shown to function as the key kinase that activates the spindle assembly checkpoint (SAC) to secure proper distribution of chromosomes to daughter cells. Here, we report the structure and functional characterization of two novel selective Mps1 inhibitors, BAY 1161909 and BAY 1217389, derived from structurally distinct chemical classes. BAY 1161909 and BAY 1217389 inhibited Mps1 kinase activity with IC50 values below 10 nmol/L while showing an excellent selectivity profile. In cellular mechanistic assays, both Mps1 inhibitors abrogated nocodazole-induced SAC activity and induced premature exit from mitosis ("mitotic breakthrough"), resulting in multinuclearity and tumor cell death. Both compounds efficiently inhibited tumor cell proliferation in vitro (IC50 nmol/L range). In vivo, BAY 1161909 and BAY 1217389 achieved moderate efficacy in monotherapy in tumor xenograft studies. However, in line with its unique mode of action, when combined with paclitaxel, low doses of Mps1 inhibitor reduced paclitaxel-induced mitotic arrest by the weakening of SAC activity. As a result, combination therapy strongly improved efficacy over paclitaxel or Mps1 inhibitor monotreatment at the respective MTDs in a broad range of xenograft models, including those showing acquired or intrinsic paclitaxel resistance. Both Mps1 inhibitors showed good tolerability without adding toxicity to paclitaxel monotherapy. These preclinical findings validate the innovative concept of SAC abrogation for cancer therapy and justify clinical proof-of-concept studies evaluating the Mps1 inhibitors BAY 1161909 and BAY 1217389 in combination with antimitotic cancer drugs to enhance their efficacy and potentially overcome resistance. Mol Cancer Ther; 15(4); 583-92. ©2016 AACR.
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany. antje.wengner@bayer.com.
authors.forename: Antje M
authors.initials: AM
authors.lastname: Wengner
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Siemeister
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Koppitz
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Schulze
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Kosemund
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Klar
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Stoeckigt
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Neuhaus
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Lienau
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bader
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Prechtl
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Marian
authors.initials: M
authors.lastname: Raschke
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Frisk
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: von Ahsen
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Michels
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Bertolt
authors.initials: B
authors.lastname: Kreft
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: von Nussbaum
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Brands
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Mumberg
authors.affiliation: Bayer Pharma AG, Drug Discovery, Berlin, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Ziegelbauer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human