title: Discovery of the 1,7-diazacarbazole class of inhibitors of checkpoint kinase 1.
abstract: Checkpoint kinase 1 (ChK1) is activated in response to DNA damage, acting to temporarily block cell cycle progression and allow for DNA repair. It is envisaged that inhibition of ChK1 will sensitize tumor cells to treatment with DNA-damaging therapies, and may enhance the therapeutic window. High throughput screening identified carboxylate-containing diarylpyrazines as a prominent hit series, but with limited biochemical potency and no cellular activity. Through a series of SAR investigations and X-ray crystallographic analysis the critical role of polar contacts with conserved waters in the kinase back pocket was established. Structure-based design, guided by in silico modeling, transformed the series to better satisfy these contacts and the novel 1,7-diazacarbazole class of inhibitors was discovered. Here we present the genesis of this novel series and the identification of GNE-783, a potent, selective and orally bioavailable inhibitor of ChK1.
authors.affiliation: Department of Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Lewis
authors.initials: L
authors.lastname: Gazzard
authors.affiliation: Department of Structural Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Brent
authors.initials: B
authors.lastname: Appleton
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: Department of Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Huifen
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Clark
authors.affiliation: Department of Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
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: Simon
authors.initials: S
authors.lastname: Goodacre
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Halladay
authors.affiliation: Department of Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Lyssikatos
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Sideris
authors.affiliation: Department of Structural Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Wiesmann
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.affiliation: Department of Structural Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Ivana
authors.initials: I
authors.lastname: Yen
authors.affiliation: Department of Biochemical and Cellular Pharmacology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
authors.forename: Shiva
authors.initials: S
authors.lastname: Malek
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001372:Aza Compounds / Q000737:chemistry*; D002227:Carbazoles / Q000737:chemistry*; D002243:Carbolines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D055808:Drug Discovery; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D000093542:Gemcitabine
chemical_list: D001372:Aza Compounds; D002227:Carbazoles; D002243:Carbolines; C000589252:GNE-783; D047428:Protein Kinase Inhibitors; D003841:Deoxycytidine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C000605871:Chek1 protein, rat; D000093542:Gemcitabine
keywords: ChK1; Checkpoint; Diazacarbazole; GNE-783; Structure-based design