title: Preparation of kinase-biased compounds in the search for lead inhibitors of kinase targets.
abstract: This work describes the preparation of approximately 13,000 compounds for rapid identification of hits in high-throughput screening (HTS). These compounds were designed as potential serine/threonine or tyrosine kinase inhibitors. The library consists of various scaffolds, e.g., purines, oxindoles, and imidazoles, whereby each core scaffold generally includes the hydrogen bond acceptor/donor properties known to be important for kinase binding. Several of these are based upon literature kinase templates, or adaptations of them to provide novelty. The routes to their preparation are outlined. A variety of automation techniques were used to prepare >500 compounds per scaffold. Where applicable, scavenger resins were employed to remove excess reagents and when necessary, preparative high performance liquid chromatography (HPLC) was used for purification. These compounds were screened against an 'in-house' kinase panel. The success rate in HTS was significantly higher than the corporate compound collection.
authors.affiliation: Millennium Pharmaceuticals R&D Limited, Granta Park, Great Abington, Cambridge CB1 6ET, United Kingdom.
authors.forename: Justine Y Q
authors.initials: JY
authors.lastname: Lai
authors.forename: Steven
authors.initials: S
authors.lastname: Langston
authors.forename: Ruth
authors.initials: R
authors.lastname: Adams
authors.forename: Rebekah E
authors.initials: RE
authors.lastname: Beevers
authors.forename: Richard
authors.initials: R
authors.lastname: Boyce
authors.forename: Svenja
authors.initials: S
authors.lastname: Burckhardt
authors.forename: James
authors.initials: J
authors.lastname: Cobb
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Ferguson
authors.forename: Eva
authors.initials: E
authors.lastname: Figueroa
authors.forename: Neil
authors.initials: N
authors.lastname: Grimster
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Henry
authors.forename: Nawaz
authors.initials: N
authors.lastname: Khan
authors.forename: Kerry
authors.initials: K
authors.lastname: Jenkins
authors.forename: Mark W
authors.initials: MW
authors.lastname: Jones
authors.forename: Robert
authors.initials: R
authors.lastname: Judkins
authors.forename: Jeremy
authors.initials: J
authors.lastname: Major
authors.forename: Abid
authors.initials: A
authors.lastname: Masood
authors.forename: James
authors.initials: J
authors.lastname: Nally
authors.forename: Helen
authors.initials: H
authors.lastname: Payne
authors.forename: Lloyd
authors.initials: L
authors.lastname: Payne
authors.forename: Gilles
authors.initials: G
authors.lastname: Raphy
authors.forename: Tony
authors.initials: T
authors.lastname: Raynham
authors.forename: John
authors.initials: J
authors.lastname: Reader
authors.forename: Valérie
authors.initials: V
authors.lastname: Reader
authors.forename: Alison
authors.initials: A
authors.lastname: Reid
authors.forename: Parminder
authors.initials: P
authors.lastname: Ruprah
authors.forename: Michael
authors.initials: M
authors.lastname: Shaw
authors.forename: Hannah
authors.initials: H
authors.lastname: Sore
authors.forename: Matthew
authors.initials: M
authors.lastname: Stirling
authors.forename: Adam
authors.initials: A
authors.lastname: Talbot
authors.forename: Jess
authors.initials: J
authors.lastname: Taylor
authors.forename: Stephen
authors.initials: S
authors.lastname: Thompson
authors.forename: Hiroki
authors.initials: H
authors.lastname: Wada
authors.forename: David
authors.initials: D
authors.lastname: Walker
mesh_terms: D015195:Drug Design; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis / Q000494:pharmacology; D009281:Naphthalenes / Q000138:chemical synthesis / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011687:Purines / Q000138:chemical synthesis / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D007093:Imidazoles; D007211:Indoles; D007546:Isoquinolines; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D011687:Purines; D011743:Pyrimidines