Faisal Amir, Mak Grace W Y, Gurden Mark D, Xavier Cristina P R, Anderhub Simon J, Innocenti Paolo, Westwood Isaac M, Naud Sébastien, Hayes Angela, Box Gary, Valenti Melanie R, De Haven Brandon Alexis K, O'Fee Lisa, Schmitt Jessica, Woodward Hannah L, Burke Rosemary, vanMontfort Rob L M, Blagg Julian, Raynaud Florence I, Eccles Suzanne A, Hoelder Swen, Linardopoulos Spiros
Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.
Breast Cancer Now, Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
Br J Cancer. 2017 Apr 25;116(9):1166-1176. doi: 10.1038/bjc.2017.75. Epub 2017 Mar 23.
The main role of the cell cycle is to enable error-free DNA replication, chromosome segregation and cytokinesis. One of the best characterised checkpoint pathways is the spindle assembly checkpoint, which prevents anaphase onset until the appropriate attachment and tension across kinetochores is achieved. MPS1 kinase activity is essential for the activation of the spindle assembly checkpoint and has been shown to be deregulated in human tumours with chromosomal instability and aneuploidy. Therefore, MPS1 inhibition represents an attractive strategy to target cancers.
To evaluate CCT271850 cellular potency, two specific antibodies that recognise the activation sites of MPS1 were used and its antiproliferative activity was determined in 91 human cancer cell lines. DLD1 cells with induced GFP-MPS1 and HCT116 cells were used in in vivo studies to directly measure MPS1 inhibition and efficacy of CCT271850 treatment.
CCT271850 selectively and potently inhibits MPS1 kinase activity in biochemical and cellular assays and in in vivo models. Mechanistically, tumour cells treated with CCT271850 acquire aberrant numbers of chromosomes and the majority of cells divide their chromosomes without proper alignment because of abrogation of the mitotic checkpoint, leading to cell death. We demonstrated a moderate level of efficacy of CCT271850 as a single agent in a human colorectal carcinoma xenograft model.
CCT271850 is a potent, selective and orally bioavailable MPS1 kinase inhibitor. On the basis of in vivo pharmacodynamic vs efficacy relationships, we predict that more than 80% inhibition of MPS1 activity for at least 24 h is required to achieve tumour stasis or regression by CCT271850.
细胞周期的主要作用是实现无差错的DNA复制、染色体分离和胞质分裂。其中一个特征最明显的检查点通路是纺锤体组装检查点，它可防止后期开始，直到在动粒上实现适当的附着和张力。MPS1激酶活性对于纺锤体组装检查点的激活至关重要，并且已证实在具有染色体不稳定性和非整倍性的人类肿瘤中其失调。因此，抑制MPS1代表了一种有吸引力的癌症靶向策略。
为了评估CCT271850的细胞活性，使用了两种识别MPS1激活位点的特异性抗体，并在91种人类癌细胞系中测定了其抗增殖活性。在体内研究中使用诱导了绿色荧光蛋白-MPS1的DLD1细胞和HCT116细胞，以直接测量MPS1抑制作用和CCT271850治疗的疗效。
在生化和细胞试验以及体内模型中，CCT271850选择性且强效地抑制MPS1激酶活性。从机制上讲，用CCT271850处理的肿瘤细胞会获得异常数量的染色体，并且由于有丝分裂检查点的废除，大多数细胞在没有正确排列的情况下分离其染色体，从而导致细胞死亡。我们在人结直肠癌异种移植模型中证明了CCT271850作为单一药物具有中等水平的疗效。
CCT271850是一种强效、选择性且口服生物可利用的MPS1激酶抑制剂。基于体内药效学与疗效的关系，我们预测CCT271850要实现肿瘤停滞或消退，需要至少24小时内对MPS1活性进行超过80%的抑制。
