Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy.
Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy.
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DOI：
10.1038/bjc.2017.75
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发表时间：
2017-04-25
影响因子：
8.8
通讯作者：
Linardopoulos S
中科院分区：
文献类型：
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作者：
Faisal A;Mak GWY;Gurden MD;Xavier CPR;Anderhub SJ;Innocenti P;Westwood IM;Naud S;Hayes A;Box G;Valenti MR;De Haven Brandon AK;O'Fee L;Schmitt J;Woodward HL;Burke R;vanMontfort RLM;Blagg J;Raynaud FI;Eccles SA;Hoelder S;Linardopoulos S
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。最具特征的检查点途径之一是纺锤体装配检查点，它可以防止后期的发生，直到在着丝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，并且已被证明在具有染色体不稳定和非整倍性的人类肿瘤中失调。因此，MPS1 抑制代表了一种针对癌症的有吸引力的策略。为了评估 CCT271850 的细胞效力，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。诱导 GFP-MPS1 的 DLD1 细胞和 HCT116 细胞用于体内研究，以直接测量 MPS1 抑制和 CCT271850 治疗的功效。 CCT271850 在生化和细胞测定以及体内模型中选择性且有效地抑制 MPS1 激酶活性。从机制上讲，用 CCT271850 处理的肿瘤细胞获得了异常数量的染色体，并且由于有丝分裂检查点的废除，大多数细胞在没有正确对齐的情况下分裂染色体，从而导致细胞死亡。我们在人类结直肠癌异种移植模型中证明了 CCT271850 作为单一药物的中等疗效。 CCT271850 是一种有效的、选择性的、口服生物可利用的 MPS1 激酶抑制剂。根据体内药效与功效关系，我们预测 CCT271850 需要在至少 24 小时内抑制超过 80% 的 MPS1 活性才能实现肿瘤停滞或消退。
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.