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

DOI: 10.1021/jm401395s DOI Help
PMID: 24256217 PMID Help

Authors: S├ębastien Naud (Cancer Research UK) , Isaac Westwood (Institute of Cancer Research, Cancer Research UK) , Amir Faisal (Cancer Research UK) , Peter Sheldrake (Cancer Research UK) , Vassilios Bavetsias (Cancer Research UK) , Butrus Atrash (Cancer Research UK) , Kwai-ming J. Cheung (Cancer Research UK) , Manjuan Liu (Cancer Research UK) , Angela Hayes (Cancer Research UK) , Jessica Schmitt (Cancer Research UK) , Amy Wood (Cancer Research UK) , Vanessa Choi (Cancer Research UK) , Kathy Boxall (Cancer Research UK) , Grace Mak (Cancer Research UK) , Mark Gurden (Breast Cancer Research) , Melanie Valenti (Cancer Research UK) , Alexis De Haven Brandon (Cancer Research UK) , Alan Henley (Cancer Research UK) , Ross Baker (Cancer Research UK) , Craig Mcandrew (Cancer Research UK)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 56 (24) , PAGES 10045 - 10065

State: Published (Approved)
Published: December 2013
Diamond Proposal Number(s): 8015

Open Access Open Access

Abstract: 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.

Journal Keywords: Oral; Aniline; Biological; Cell; Dose-Response; Drug; Drug; Heterocyclic; 2-Ring; Models; Molecular; Protein; Protein-Serine-Threonine; Protein-Tyrosine; Structure-Activity Relationship

Subject Areas: Biology and Bio-materials, Medicine


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