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

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• 作者：Paolo Innocenti ; Hannah L. Woodward ; Savade Solanki ; Sébastien Naud ; Isaac M. Westwood ; Nora Cronin ; Angela Hayes ; Jennie Roberts ; Alan T. Henley ; Ross Baker ; Amir Faisal ; Grace Wing-Yan Mak ; Gary Box ; Melanie Valenti ; Alexis De Haven Brandon ; Lisa O’Fee ; Harry Saville ; Jessica Schmitt ; Berry Matijssen ; Rosemary Burke ; Rob L. M. van Montfort ; Florence I. Raynaud ; Suzanne A. Eccles ; Spiros Linardopoulos ; Julian Blagg ; Swen Hoelder
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 28, 2016
• 年：2016
• 卷：59
• 期：8
• 页码：3671-3688
• 全文大小：918K
• 年卷期：0
• ISSN：1520-4804

文摘

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.