Download MendeleyRapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach.
Innocenti, P., Woodward, H.L., Solanki, S., Naud, S., Westwood, I.M., Cronin, N., Hayes, A., Roberts, J., Henley, A.T., Baker, R., Faisal, A., Mak, G.W., Box, G., Valenti, M., De Haven Brandon, A., O'Fee, L., Saville, H., Schmitt, J., Matijssen, B., Burke, R., van Montfort, R.L., Raynaud, F.I., Eccles, S.A., Linardopoulos, S., Blagg, J., Hoelder, S.(2016) J Med Chem 59: 3671-3688
- PubMed: 27055065
- DOI: https://doi.org/10.1021/acs.jmedchem.5b01811
- Primary Citation of Related Structures:
5EH0, 5EHY, 5EI2, 5EI6, 5EI8 - PubMed Abstract:
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.
Organizational Affiliation:
Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
