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

[Image: see text] 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...

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Autores principales: Naud, Sébastien, Westwood, Isaac M., Faisal, Amir, Sheldrake, Peter, Bavetsias, Vassilios, Atrash, Butrus, Cheung, Kwai-Ming J., Liu, Manjuan, Hayes, Angela, Schmitt, Jessica, Wood, Amy, Choi, Vanessa, Boxall, Kathy, Mak, Grace, Gurden, Mark, Valenti, Melanie, de Haven Brandon, Alexis, Henley, Alan, Baker, Ross, McAndrew, Craig, Matijssen, Berry, Burke, Rosemary, Hoelder, Swen, Eccles, Suzanne A., Raynaud, Florence I., Linardopoulos, Spiros, van Montfort, Rob L. M., Blagg, Julian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2013
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873811/
https://www.ncbi.nlm.nih.gov/pubmed/24256217
http://dx.doi.org/10.1021/jm401395s
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author Naud, Sébastien
Westwood, Isaac M.
Faisal, Amir
Sheldrake, Peter
Bavetsias, Vassilios
Atrash, Butrus
Cheung, Kwai-Ming J.
Liu, Manjuan
Hayes, Angela
Schmitt, Jessica
Wood, Amy
Choi, Vanessa
Boxall, Kathy
Mak, Grace
Gurden, Mark
Valenti, Melanie
de Haven Brandon, Alexis
Henley, Alan
Baker, Ross
McAndrew, Craig
Matijssen, Berry
Burke, Rosemary
Hoelder, Swen
Eccles, Suzanne A.
Raynaud, Florence I.
Linardopoulos, Spiros
van Montfort, Rob L. M.
Blagg, Julian
author_facet Naud, Sébastien
Westwood, Isaac M.
Faisal, Amir
Sheldrake, Peter
Bavetsias, Vassilios
Atrash, Butrus
Cheung, Kwai-Ming J.
Liu, Manjuan
Hayes, Angela
Schmitt, Jessica
Wood, Amy
Choi, Vanessa
Boxall, Kathy
Mak, Grace
Gurden, Mark
Valenti, Melanie
de Haven Brandon, Alexis
Henley, Alan
Baker, Ross
McAndrew, Craig
Matijssen, Berry
Burke, Rosemary
Hoelder, Swen
Eccles, Suzanne A.
Raynaud, Florence I.
Linardopoulos, Spiros
van Montfort, Rob L. M.
Blagg, Julian
author_sort Naud, Sébastien
collection PubMed
description [Image: see text] 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.
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spelling pubmed-38738112013-12-28 Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1) Naud, Sébastien Westwood, Isaac M. Faisal, Amir Sheldrake, Peter Bavetsias, Vassilios Atrash, Butrus Cheung, Kwai-Ming J. Liu, Manjuan Hayes, Angela Schmitt, Jessica Wood, Amy Choi, Vanessa Boxall, Kathy Mak, Grace Gurden, Mark Valenti, Melanie de Haven Brandon, Alexis Henley, Alan Baker, Ross McAndrew, Craig Matijssen, Berry Burke, Rosemary Hoelder, Swen Eccles, Suzanne A. Raynaud, Florence I. Linardopoulos, Spiros van Montfort, Rob L. M. Blagg, Julian J Med Chem [Image: see text] 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. American Chemical Society 2013-11-20 2013-12-27 /pmc/articles/PMC3873811/ /pubmed/24256217 http://dx.doi.org/10.1021/jm401395s Text en Copyright © 2013 American Chemical Society Terms of Use CC-BY (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html)
spellingShingle Naud, Sébastien
Westwood, Isaac M.
Faisal, Amir
Sheldrake, Peter
Bavetsias, Vassilios
Atrash, Butrus
Cheung, Kwai-Ming J.
Liu, Manjuan
Hayes, Angela
Schmitt, Jessica
Wood, Amy
Choi, Vanessa
Boxall, Kathy
Mak, Grace
Gurden, Mark
Valenti, Melanie
de Haven Brandon, Alexis
Henley, Alan
Baker, Ross
McAndrew, Craig
Matijssen, Berry
Burke, Rosemary
Hoelder, Swen
Eccles, Suzanne A.
Raynaud, Florence I.
Linardopoulos, Spiros
van Montfort, Rob L. M.
Blagg, Julian
Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1)
title Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1)
title_full Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1)
title_fullStr Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1)
title_full_unstemmed Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1)
title_short Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1)
title_sort structure-based design of orally bioavailable 1h-pyrrolo[3,2-c]pyridine inhibitors of mitotic kinase monopolar spindle 1 (mps1)
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873811/
https://www.ncbi.nlm.nih.gov/pubmed/24256217
http://dx.doi.org/10.1021/jm401395s
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