Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1)

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• 作者：Sébastien Naud ; Isaac M. Westwood ; Amir Faisal ; Peter Sheldrake ; Vassilios Bavetsias ; Butrus Atrash ; Kwai-Ming J. Cheung ; Manjuan Liu ; Angela Hayes ; Jessica Schmitt ; Amy Wood ; Vanessa Choi ; Kathy Boxall ; Grace Mak ; Mark Gurden ; Melanie Valenti ; Alexis de Haven Brandon ; Alan Henley ; Ross Baker ; Craig McAndrew ; Berry Matijssen ; Rosemary Burke ; Swen Hoelder ; Suzanne A. Eccles ; Florence I. Raynaud ; Spiros Linardopoulos ; Rob L. M. van Montfort ; Julian Blagg
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 27, 2013
• 年：2013
• 卷：56
• 期：24
• 页码：10045-10065
• 全文大小：1103K
• ISSN：1520-4804

文摘

The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly overexpressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition.