title: Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1.
abstract: Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.
authors.forename: Lewis
authors.initials: L
authors.lastname: Gazzard
authors.affiliation: ∇Argenta, A Charles River Company, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Williams
authors.forename: Huifen
authors.initials: H
authors.lastname: Chen
authors.affiliation: ∇Argenta, A Charles River Company, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Axford
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Blackwood
authors.affiliation: ∇Argenta, A Charles River Company, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Brenda
authors.initials: B
authors.lastname: Burton
authors.affiliation: ∇Argenta, A Charles River Company, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Kerry
authors.initials: K
authors.lastname: Chapman
authors.affiliation: ∇Argenta, A Charles River Company, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Crackett
authors.forename: Joy
authors.initials: J
authors.lastname: Drobnick
authors.affiliation: ∇Argenta, A Charles River Company, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Charles
authors.initials: C
authors.lastname: Ellwood
authors.forename: Jennifer
authors.initials: J
authors.lastname: Epler
authors.forename: Michael
authors.initials: M
authors.lastname: Flagella
authors.affiliation: ∇Argenta, A Charles River Company, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Gancia
authors.affiliation: ∇Argenta, A Charles River Company, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gill
authors.affiliation: ∇Argenta, A Charles River Company, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Goodacre
authors.forename: Jason
authors.initials: J
authors.lastname: Halladay
authors.affiliation: ∇Argenta, A Charles River Company, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Joanne
authors.initials: J
authors.lastname: Hewitt
authors.affiliation: ∇Argenta, A Charles River Company, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Hazel
authors.initials: H
authors.lastname: Hunt
authors.forename: Samuel
authors.initials: S
authors.lastname: Kintz
authors.forename: Joseph
authors.initials: J
authors.lastname: Lyssikatos
authors.affiliation: ∇Argenta, A Charles River Company, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Calum
authors.initials: C
authors.lastname: Macleod
authors.affiliation: ∇Argenta, A Charles River Company, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Major
authors.affiliation: ∇Argenta, A Charles River Company, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Médard
authors.affiliation: ∇Argenta, A Charles River Company, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Raman
authors.initials: R
authors.lastname: Narukulla
authors.forename: Judi
authors.initials: J
authors.lastname: Ramiscal
authors.forename: Stephen
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: ∇Argenta, A Charles River Company, 8-9 Spire Green Centre, Harlow, Essex CM19 5TR, United Kingdom.
authors.forename: Eileen
authors.initials: E
authors.lastname: Seward
authors.forename: Christian
authors.initials: C
authors.lastname: Wiesmann
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: Sharon
authors.initials: S
authors.lastname: Yee
authors.forename: Ivana
authors.initials: I
authors.lastname: Yen
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D001372:Aza Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002227:Carbazoles / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D004285:Dogs; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D051381:Rats
chemical_list: D001372:Aza Compounds; D002227:Carbazoles; D002800:Cholinesterase Inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C000605871:Chek1 protein, rat; D000110:Acetylcholinesterase