title: 6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases.
abstract: Analysis of the x-ray crystal structure of mono-substituted acetylenic thienopyrimidine 6 complexed with the ErbB family enzyme ErbB-4 revealed a covalent bond between the terminal carbon of the acetylene moiety and the sulfhydryl group of Cys-803 at the solvent interface. The identification of this covalent adduct suggested that acetylenic thienopyrimidine 6 and related analogs might also be capable of forming an analogous covalent adduct with EGFR, which has a conserved cysteine (797) near the ATP binding pocket. To test this hypothesis, we treated a truncated, catalytically competent form of EGFR (678-1020) with a structurally related propargylic amine (8). An investigation of the resulting complex by mass spectrometry revealed the formation of a covalent complex of thienopyrimidine 8 with Cys-797 of EGFR. This finding enabled us to readily assess the irreversibility of various inhibitors and also facilitated a structure-activity relationship understanding of the covalent modifying potential and biological activity of a series of acetylenic thienopyrimidine compounds with potent antitumor activity. Several ErbB family enzyme and cell potent 6-ethynyl thienopyrimidine kinase inhibitors were found to form covalent adducts with EGFR.
authors.affiliation: Department of Assay Development, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
authors.forename: Edgar R
authors.initials: ER
authors.lastname: Wood
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Shewchuk
authors.forename: Byron
authors.initials: B
authors.lastname: Ellis
authors.forename: Perry
authors.initials: P
authors.lastname: Brignola
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Brashear
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Caferro
authors.forename: Scott H
authors.initials: SH
authors.lastname: Dickerson
authors.forename: Hamilton D
authors.initials: HD
authors.lastname: Dickson
authors.forename: Kelly H
authors.initials: KH
authors.lastname: Donaldson
authors.forename: Michael
authors.initials: M
authors.lastname: Gaul
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: Anne M
authors.initials: AM
authors.lastname: Hassell
authors.forename: Barry
authors.initials: B
authors.lastname: Keith
authors.forename: Robert
authors.initials: R
authors.lastname: Mullin
authors.forename: Kimberly G
authors.initials: KG
authors.lastname: Petrov
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reno
authors.forename: David W
authors.initials: DW
authors.lastname: Rusnak
authors.forename: Sarva M
authors.initials: SM
authors.lastname: Tadepalli
authors.forename: John C
authors.initials: JC
authors.lastname: Ulrich
authors.forename: Craig D
authors.initials: CD
authors.lastname: Wagner
authors.forename: Dana E
authors.initials: DE
authors.lastname: Vanderwall
authors.forename: Alex G
authors.initials: AG
authors.lastname: Waterson
authors.forename: Jon D
authors.initials: JD
authors.lastname: Williams
authors.forename: Wendy L
authors.initials: WL
authors.lastname: White
authors.forename: David E
authors.initials: DE
authors.lastname: Uehling
mesh_terms: D000480:Alkynes / Q000378:metabolism*; D000814:Aniline Compounds / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D007510:Isatin / Q000031:analogs & derivatives / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000378:metabolism* / Q000633:toxicity; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000480:Alkynes; D000814:Aniline Compounds; D011743:Pyrimidines; C116442:propargylic sulfone; C476003:thienopyrimidine; D007510:Isatin; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases