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Rapid Discovery of Pyrido[3,4- d ]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach

DOI: 10.1021/acs.jmedchem.5b01811 DOI Help

Authors: Paolo Innocenti (Cancer Research UK) , Hannah L. Woodward (Cancer Research UK) , Savade Solanki (Cancer Research UK) , Sébastien Naud (Cancer Research UK) , Isaac Westwood (Institute of Cancer Research, Cancer Research UK) , Nora Cronin (Institute of Cancer Research) , Angela Hayes (Cancer Research UK) , Jennie Roberts (Cancer Research UK) , Alan T. Henley (Cancer Research UK) , Ross Baker (Cancer Research UK) , Amir Faisal (Cancer Research UK) , Grace Wing-yan Mak (Cancer Research UK) , Gary Box (Cancer Research UK) , Melanie Valenti (Cancer Research UK) , Alexis De Haven Brandon (Cancer Research UK) , Lisa O’ Fee (Cancer Research UK) , Harry Saville (Cancer Research UK) , Jessica Schmitt (Cancer Research UK) , Berry Matijssen (Cancer Research UK) , Rosemary Burke (Cancer Research UK) , Rob Van Montfort (Cancer Research UK; The Institute of Cancer Research) , Florence I. Raynaud (Cancer Research UK) , Suzanne A. Eccles (Cancer Research UK) , Spiros Linardopoulos (Cancer Research UK) , Julian Blagg (Cancer Research UK) , Swen Hoelder (Cancer Research UK)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: April 2016

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.

Subject Areas: Biology and Bio-materials

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography