title: Structure-based design of orally bioavailable 1H-pyrrolo[3,2-c]pyridine inhibitors of mitotic kinase monopolar spindle 1 (MPS1).
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.
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , London SM2 5NG, United Kingdom.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Naud
authors.forename: Isaac M
authors.initials: IM
authors.lastname: Westwood
authors.forename: Amir
authors.initials: A
authors.lastname: Faisal
authors.forename: Peter
authors.initials: P
authors.lastname: Sheldrake
authors.forename: Vassilios
authors.initials: V
authors.lastname: Bavetsias
authors.forename: Butrus
authors.initials: B
authors.lastname: Atrash
authors.forename: Kwai-Ming J
authors.initials: KM
authors.lastname: Cheung
authors.forename: Manjuan
authors.initials: M
authors.lastname: Liu
authors.forename: Angela
authors.initials: A
authors.lastname: Hayes
authors.forename: Jessica
authors.initials: J
authors.lastname: Schmitt
authors.forename: Amy
authors.initials: A
authors.lastname: Wood
authors.forename: Vanessa
authors.initials: V
authors.lastname: Choi
authors.forename: Kathy
authors.initials: K
authors.lastname: Boxall
authors.forename: Grace
authors.initials: G
authors.lastname: Mak
authors.forename: Mark
authors.initials: M
authors.lastname: Gurden
authors.forename: Melanie
authors.initials: M
authors.lastname: Valenti
authors.forename: Alexis
authors.initials: A
authors.lastname: de Haven Brandon
authors.forename: Alan
authors.initials: A
authors.lastname: Henley
authors.forename: Ross
authors.initials: R
authors.lastname: Baker
authors.forename: Craig
authors.initials: C
authors.lastname: McAndrew
authors.forename: Berry
authors.initials: B
authors.lastname: Matijssen
authors.forename: Rosemary
authors.initials: R
authors.lastname: Burke
authors.forename: Swen
authors.initials: S
authors.lastname: Hoelder
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.forename: Spiros
authors.initials: S
authors.lastname: Linardopoulos
authors.forename: Rob L M
authors.initials: RL
authors.lastname: van Montfort
authors.forename: Julian
authors.initials: J
authors.lastname: Blagg
mesh_terms: D000284:Administration, Oral; D000814:Aniline Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000814:Aniline Compounds; D018797:Cell Cycle Proteins; D006574:Heterocyclic Compounds, 2-Ring; D047428:Protein Kinase Inhibitors; C586722:tert-butyl 6-(2-chloro-4-(1-methyl-1H-imidazol-5-yl)phenylamino)-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo(3,2-c)pyridine-1-carboxylate; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human