1. Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach
- Author
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Isaac M. Westwood, Amir Faisal, Lisa O’Fee, Melanie Valenti, Julian Blagg, Rob L. M. van Montfort, Berry Matijssen, Nora Cronin, Jessica Schmitt, Jennie Roberts, Sébastien Naud, Suzanne A. Eccles, Harry Saville, Angela Hayes, Gary Box, Grace Mak, Florence I. Raynaud, Alan T. Henley, Paolo Innocenti, Swen Hoelder, Hannah Woodward, Ross Baker, Savade Solanki, Alexis De Haven Brandon, Spiros Linardopoulos, and Rosemary Burke
- Subjects
0301 basic medicine ,Molecular Structure ,Transition (genetics) ,Chemistry ,Drug discovery ,Cell Cycle Proteins ,Protein Serine-Threonine Kinases ,Protein-Tyrosine Kinases ,Pharmacology ,Cell biology ,03 medical and health sciences ,Spindle checkpoint ,030104 developmental biology ,0302 clinical medicine ,In vivo ,Centrosome ,030220 oncology & carcinogenesis ,Drug Discovery ,Cancer cell ,Molecular Medicine ,Protein Kinase Inhibitors ,Metaphase ,Anaphase - 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.
- Published
- 2016