1578243-86-3Relevant academic research and scientific papers
Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach
Innocenti, Paolo,Woodward, Hannah L.,Solanki, Savade,Naud, Sébastien,Westwood, Isaac M.,Cronin, Nora,Hayes, Angela,Roberts, Jennie,Henley, Alan T.,Baker, Ross,Faisal, Amir,Mak, Grace Wing-Yan,Box, Gary,Valenti, Melanie,De Haven Brandon, Alexis,O'Fee, Lisa,Saville, Harry,Schmitt, Jessica,Matijssen, Berry,Burke, Rosemary,Van Montfort, Rob L. M.,Raynaud, Florence I.,Eccles, Suzanne A.,Linardopoulos, Spiros,Blagg, Julian,Hoelder, Swen
, p. 3671 - 3688 (2016/05/19)
Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which translates into biomarker modulation in an in vivo human tumor xenograft model.
INHIBITOR COMPOUNDS
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Paragraph 00233-00236, (2014/03/26)
The present invention relates to compounds of formula (I), wherein R, R, Ar, W, X and Z are all as defined herein. The compounds of the present invention are known to inhibit the spindle checkpoint function of Monospindle 1 (Mps1 - also known as TTK) kinases either directly or indirectly via interaction with the Mps1 kinase itself. In particular, the present invention relates to the use of these compounds as therapeutic agents for the treatment and/or prevention of proliferative diseases, such as cancer. The present invention also relates to processes for the preparation of these compounds, and to pharmaceutical compositions comprising them
