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

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

  • J Med Chem. 2016 Apr 28;59(8):3671-88. doi: 10.1021/acs.jmedchem.5b01811.
Paolo Innocenti 1,  Hannah L Woodward 1,  Savade Solanki 1,  Sébastien Naud 1,  Isaac M Westwood 1,  Nora Cronin,  Angela Hayes 1,  Jennie Roberts 1,  Alan T Henley 1,  Ross Baker 1,  Amir Faisal 1,  Grace Wing-Yan Mak 1,  Gary Box 1,  Melanie Valenti 1,  Alexis De Haven Brandon 1,  Lisa O'Fee 1,  Harry Saville 1,  Jessica Schmitt 1,  Berry Matijssen 1,  Rosemary Burke 1,  Rob L M van Montfort 1,  Florence I Raynaud 1,  Suzanne A Eccles 1,  Spiros Linardopoulos 1,  Julian Blagg 1,  Swen Hoelder 1
Affiliations

Affiliation

  • 1 Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
PMID: 27055065 DOI: 10.1021/acs.jmedchem.5b01811
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12862
    98.55%, MPS1抑制剂
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