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

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.

单极纺锤体1（monopolar spindle 1, MPS1）激酶抑制是一种新型癌症治疗策略：其并非阻滞肿瘤细胞的细胞周期，而是驱动肿瘤细胞进入有丝分裂，无视DNA损伤以及未附着/错附着染色体的存在，最终引发非整倍性与细胞死亡。本研究以鉴定MPS1抑制剂为目标，优化工作的起始点源自两个不同化学系列的高通量筛选（high-throughput screening, HTS）命中化合物——三唑并吡啶类（triazolopyridines）与咪唑并吡嗪类（imidazopyrazines）。三唑并吡啶系列最初的核心问题在于其HTS命中化合物的活性中等；而咪唑并吡嗪系列的活性高出10倍以上，但在项目早期阶段存在代谢稳定性不佳的缺陷。本文概述了这两个命中系列向临床候选化合物BAY 1161909与BAY 1217389的演化历程，并阐明两款临床候选化合物如何结合MPS1激酶的ATP结合位点（ATP site）：二者通过不同的结合相互作用靶向不同的口袋，同时介绍了它们的合成方法以及在精选体内药效模型中的临床前表征。