Characterisation of CCT271850, a selective, oral and potent MPS1 inhibitor, used to directly measure in vivo MPS1 inhibition vs therapeutic efficacy.
Date
2017-04-25ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Subject
Cell Line, Tumor
HCT116 Cells
Animals
Humans
Mice
Neoplasms
Protein-Serine-Threonine Kinases
Cell Cycle Proteins
Protein Kinase Inhibitors
Xenograft Model Antitumor Assays
Protein-Tyrosine Kinases
M Phase Cell Cycle Checkpoints
Heterocyclic Compounds, 4 or More Rings
Research team
Drug Target Discovery
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 1
Medicinal Chemistry 4 (including Analytical Chemistry)
Hit Discovery & Structural Design
Language
eng
Date accepted
2017-03-01
License start date
2017-04
Citation
British journal of cancer, 2017, 116 (9), pp. 1166 - 1176
Publisher
NATURE PUBLISHING GROUP