An Open-label Phase I Dose-escalation Study to Characterize the Safety, Tolerability, Pharmacokinetics, and Maximum Tolerated Dose of Oral BAY1161909 in Combination With Weekly Intravenous Paclitaxel Given in an Intermittent Dosing Schedule in Subjects With Advanced Malignancies
Determine the safety, tolerability, maximum tolerated dose (MTD), and recommended Phase II dose (RP2D) of BAY1161909 in combination with paclitaxel in subjects with advanced malignancies.
Treating Cancer by Spindle Assembly Checkpoint Abrogation: Discovery of Two Clinical Candidates, BAY 1161909 and BAY 1217389, Targeting MPS1 Kinase.
1区 · 医学
作者: Volker K Schulze ; Ulrich Klar ; Dirk Kosemund ; Antje M Wengner ; Gerhard Siemeister ; Detlef Stöckigt ; Roland Neuhaus ; Philip Lienau ; Benjamin Bader ; Stefan Prechtl ; Simon J Holton ; Hans Briem ; Tobias Marquardt ; Hartmut Schirok ; Rolf Jautelat ; Rolf Bohlmann ; Duy Nguyen ; Amaury E Fernández-Montalván ; Ulf Bömer ; Uwe Eberspaecher ; Michael Brüning ; Olaf Döhr ; Marian Raschke ; Bertolt Kreft ; Dominik Mumberg ; Karl Ziegelbauer ; Michael Brands ; Franz von Nussbaum ; Marcus Koppitz
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.
2018-10-01·Annals of oncology : official journal of the European Society for Medical Oncology1区 · 医学
First-in-human study of the monopolar spindle 1 (Mps1) kinase inhibitor BAY 1161909 in combination with paclitaxel in subjects with advanced malignancies.
1区 · 医学
作者: P Lorusso ; S P Chawla ; J Bendell ; A F Shields ; G Shapiro ; P Rajagopalan ; C Cyris ; I Bruns ; J Mei ; F Souza ; D Rasco ; J P Eder ; A W Tolcher
2017-07-07·Journal of Molecular Biology2区 · 生物学
Target Residence Time-Guided Optimization on TTK Kinase Results in Inhibitors with Potent Anti-Proliferative Activity
2区 · 生物学
作者: Uitdehaag, Joost C. M. ; de Man, Jos ; Willemsen-Seegers, Nicole ; Prinsen, Martine B. W. ; Libouban, Marion A. A. ; Sterrenburg, Jan Gerard ; de Wit, Joeri J. P. ; de Vetter, Judith R. F. ; de Roos, Jeroen A. D. M. ; Buijsman, Rogier C. ; Zaman, Guido J. R.
The protein kinase threonine tyrosine kinase (TTK; also known as Mps1) is a critical component of the spindle assembly checkpoint and a promising drug target for the treatment of aggressive cancers, such as triple negative breast cancer. While the first TTK inhibitors have entered clinical trials, little is known about how the inhibition of TTK with small-molecule compounds affects cellular activity. We studied the selective TTK inhibitor NTRC 0066-0, which was developed in our own laboratory, together with 11 TTK inhibitors developed by other companies, including Mps-BAY2b, BAY 1161909, BAY 1217389 (Bayer), TC-Mps1-12 (Shionogi), and MPI-0479605 (Myrexis). Parallel testing shows that the cellular activity of these TTK inhibitors correlates with their binding affinity to TTK and, more strongly, with target residence time. TTK inhibitors are therefore an example where target residence time determines activity in in vitro cellular assays. X-ray structures and thermal stability experiments reveal that the most potent compounds induce a shift of the glycine-rich loop as a result of binding to the catalytic lysine at position 553. This "lysine trap" disrupts the catalytic machinery. Based on these insights, we developed TTK inhibitors, based on a (5,6-dihydro)pyrimido[4,5-e]indolizine scaffold, with longer target residence times, which further exploit an allosteric pocket surrounding Lys553. Their binding mode is new for kinase inhibitors and can be classified as hybrid Type I/Type III. These inhibitors have very potent anti-proliferative activity that rivals classic cytotoxic therapy. Our findings will open up new avenues for more applications for TTK inhibitors in cancer treatment.