Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , London SM2 5NG, United Kingdom.
J Med Chem. 2013 Dec 27;56(24):10045-65. doi: 10.1021/jm401395s. Epub 2013 Dec 2.
The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly overexpressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition.
蛋白激酶 MPS1 是纺锤体组装检查点信号的关键组成部分，在许多人类癌症中异常过表达。MPS1 是染色体不稳定和非整倍体肿瘤中过度表达的前 25 种基因之一。PTEN 缺陷的乳腺癌细胞对 MPS1 的存活特别依赖，使其成为肿瘤学中一个重要的研究目标。我们报告了基于 1H-吡咯并[3,2-c]吡啶支架的强效和选择性 MPS1 抑制剂的发现和优化，该抑制剂由基于结构的设计和 MPS1 抑制的细胞特征引导，导致 65（CCT251455）。这种强效和选择性的化学工具稳定了 MPS1 的无活性构象，使激活环呈与 ATP 和底物肽结合不兼容的方式排列；它显示出有利的口服药代动力学特征，在 HCT116 人肿瘤异种移植模型中显示出剂量依赖性的 MPS1 抑制作用，并且是一种有吸引力的工具化合物，可以进一步阐明 MPS1 抑制的治疗潜力。
