title: Extended structure-activity study of thienopyrimidine-based EGFR inhibitors with evaluation of drug-like properties.
abstract: Thieno[2,3-d]pyrimidines are attractive derivatives for cancer treatment, among others through regulation of the epidermal growth factor receptor tyrosine kinase (EGFR-TK). In an extended SAR study, 44 new compounds of this class have been evaluated as inhibitors, while simultaneously focussing on ADME properties. Through the application of bioisosters, hybrid structures, solubilizing tails, and a combination approach several successful alterations in terms of activity and physiochemical properties were accomplished. Compounds based on benzylamines were found superior to aniline hybrid structures with respect to activity and ADME profile. Exploration of the former class revealed meta- and para amides as favourable 6-aryl substituents, contributing to an increase in activity and acting as a linker for solubilizing tails. Next, combinations of activity-inducing groups on the same scaffold resulted in new drug candidates. Compounds containing 6-aryls with the (2-(dimethylamino)ethyl)carbamoyl substituent were found equipotent to Erlotinib. Compared to this commercial drug, improved solubility and metabolic stability were observed. However, the thieno[2,3-d]pyrimidines with a solubilizing tail was by Caco-2 experiments found to have permeability issues, making further drug development difficult. Selected compounds were further analysed for toxicity and teratogenicity in zebrafish embryos. Two thienopyrimidines were both found to be less lethal than Erlotinib and to perform as well in terms of teratogenicity. Finally, the most promising thienopyrimidine drug was evaluated in a panel of human cancer cell lines, showing a clear potential for thienopyrimidines as anti-cancer agents.
authors.affiliation: Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: steffen.bugge@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: audun.f.buene@ntnu.no.
authors.forename: Audun Formo
authors.initials: AF
authors.lastname: Buene
authors.affiliation: Kavli Institute for Systems Neuroscience and Center for Neural Computation, Norwegian University of Science and Technology, Olav Kyrres gate 9, MTFS, NO-7491 Trondheim, Norway. Electronic address: nathalie.jurisch-yaksi@ntnu.no.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jurisch-Yaksi
authors.affiliation: Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: ingriumoen@gmail.com.
authors.forename: Ingri Ullestad
authors.initials: IU
authors.lastname: Moen
authors.affiliation: Department of Chemistry, Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway. Electronic address: ellenmsk@stud.ntnu.no.
authors.forename: Ellen Martine
authors.initials: EM
authors.lastname: Skjønsfjell
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: D000814:Aniline Compounds / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001596:Benzylamines / Q000737:chemistry; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004625:Embryo, Nonmammalian / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D018675:Toxicity Tests; D015027:Zebrafish / Q000196:embryology
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001596:Benzylamines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C476003:thienopyrimidine; C030796:benzylamine; C512478:EGFR protein, human; D066246:ErbB Receptors; C023650:aniline
keywords: ADME; EGFR; Erlotinib; Gefitinib; Structure–activity relationship (SAR); Thieno[2,3-d]pyrimidine; Zebrafish