title: Structure-activity study leading to identification of a highly active thienopyrimidine based EGFR inhibitor.
abstract: Based on the thieno[2,3-d]pyrimidine scaffold, a series of new 4-amino-6-aryl thienopyrimidines have been prepared and evaluated as EGFR tyrosine kinase inhibitors. The in vitro activity was found to depend strongly on the substitution pattern in the 6-aryl ring, the stereochemistry, and the basicity at the secondary 4-amino group. A stepwise optimization by combination of active fragments led to the discovery of three structures with EGFR IC50 < 1 nM. The most potent drug candidate had an IC50 of 0.3 nM towards EGFR and its mutants L858R and L861Q. Studies using human cancer cell lines and an EGFR-L858R reporter cell system revealed good cellular potency, verifying the identified thienopyrimidines as promising lead structures.
authors.affiliation: Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: Steffen.Bugge@chem.ntnu.no.
authors.forename: Steffen
authors.initials: S
authors.lastname: Bugge
authors.affiliation: Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: Svein.Jacob.Kaspersen@chem.ntnu.no.
authors.forename: Svein Jacob
authors.initials: SJ
authors.lastname: Kaspersen
authors.affiliation: Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: synnelar@gmail.com.
authors.forename: Synne
authors.initials: S
authors.lastname: Larsen
authors.affiliation: Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Prinsesse Kristinas Gate 1, NO-7491 Trondheim, Norway. Electronic address: unni.nonstad@ntnu.no.
authors.forename: Unni
authors.initials: U
authors.lastname: Nonstad
authors.affiliation: Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Prinsesse Kristinas Gate 1, NO-7491 Trondheim, Norway; Sør-Trøndelag University College, Erling Skjalgssons Gate 1, NO-7004 Trondheim, Norway. Electronic address: geir.bjorkoy@hist.no.
authors.forename: Geir
authors.initials: G
authors.lastname: Bjørkøy
authors.affiliation: Sør-Trøndelag University College, E.C. Dahls Gate 2, NO-7004 Trondheim, Norway. Electronic address: eirik.sundby@hist.no.
authors.forename: Eirik
authors.initials: E
authors.lastname: Sundby
authors.affiliation: Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: bard.helge.hoff@chem.ntnu.no.
authors.forename: Bård Helge
authors.initials: BH
authors.lastname: Hoff
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001596:Benzylamines / Q000737:chemistry; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001596:Benzylamines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C476003:thienopyrimidine; C030796:benzylamine; D066246:ErbB Receptors
keywords: Benzylamine; EGFR-TK; Erlotinib; SAR; Suzuki-coupling; Thienopyrimidine