title: Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach.
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.
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Paolo
authors.initials: P
authors.lastname: Innocenti
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Woodward
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Savade
authors.initials: S
authors.lastname: Solanki
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Naud
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Isaac M
authors.initials: IM
authors.lastname: Westwood
authors.forename: Nora
authors.initials: N
authors.lastname: Cronin
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Angela
authors.initials: A
authors.lastname: Hayes
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Jennie
authors.initials: J
authors.lastname: Roberts
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Henley
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Ross
authors.initials: R
authors.lastname: Baker
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Amir
authors.initials: A
authors.lastname: Faisal
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Grace Wing-Yan
authors.initials: GW
authors.lastname: Mak
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Gary
authors.initials: G
authors.lastname: Box
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Melanie
authors.initials: M
authors.lastname: Valenti
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Alexis
authors.initials: A
authors.lastname: De Haven Brandon
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Lisa
authors.initials: L
authors.lastname: O'Fee
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Harry
authors.initials: H
authors.lastname: Saville
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Jessica
authors.initials: J
authors.lastname: Schmitt
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Berry
authors.initials: B
authors.lastname: Matijssen
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Burke
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Rob L M
authors.initials: RL
authors.lastname: van Montfort
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Spiros
authors.initials: S
authors.lastname: Linardopoulos
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Julian
authors.initials: J
authors.lastname: Blagg
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
authors.forename: Swen
authors.initials: S
authors.lastname: Hoelder
mesh_terms: D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D055808:Drug Discovery; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human