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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.

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Publication Date
2016-04-07
ICR Author
Raynaud, Florence
Linardopoulos, Spyridon
Van Montfort, Robert
Hoelder, Swen
Blagg, Julian
Burke, Rosemary
Author
Innocenti, P
Woodward, HL
Solanki, S
Naud, S
Westwood, IM
Cronin, N
Hayes, A
Roberts, J
Henley, AT
Baker, R
Faisal, A
Mak, GW-Y
Box, G
Valenti, M
De Haven Brandon, A
O'Fee, L
Saville, H
Schmitt, J
Matijssen, B
Burke, R
van Montfort, RLM
Raynaud, FI
Eccles, SA
Linardopoulos, S
Blagg, J
Hoelder, S
Type
Journal Article
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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.
URL
https://repository.icr.ac.uk/handle/internal/233
Collections
  • Breast Cancer Research
  • Cancer Therapeutics
  • Structural Biology
Licenseref URL
https://creativecommons.org/licenses/by/4.0
Version of record
10.1021/acs.jmedchem.5b01811
Subject
Protein-Serine-Threonine Kinases
Cell Cycle Proteins
Protein Kinase Inhibitors
Molecular Structure
Protein-Tyrosine Kinases
Drug Discovery
Research team
Drug Target Discovery
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Medicinal Chemistry 1
Medicinal Chemistry 4 (including Analytical Chemistry)
Hit Discovery & Structural Design
Language
eng
Date accepted
2016-03-01
License start date
2016-04-07
Citation
Journal of medicinal chemistry, 2016, 59 (8), pp. 3671 - 3688

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