title: Inhibition of epidermal growth factor receptor activity by two pyrimidopyrimidine derivatives.
abstract: Overexpression of the epidermal growth factor receptors (EGFRs) and human epidermal growth factor receptor 2 occurs frequently in human cancers and is associated with aggressive tumor behavior and poor patient prognosis. We have investigated the effects in vitro and in vivo of a new class of inhibitor molecules on the growth of several human cancer cell lines. BIBX1382 [N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine] and BIBU1361 [(3-chloro-4-fluoro-phenyl)-[6-(4-diethylaminomethyl-piperidin-1yl)-pyrimido[5,4-d]pyrimidin-4-yl]-amine] are two new selective EGFR kinase inhibitors that do not block the activity of other tyrosine kinases. BIBU1361 blocked epidermal growth factor-induced phosphorylation of EGFR and also prevented downstream responses such as mitogen-activated protein kinase kinase (MAPK/extracellular signal-regulated kinase kinase) and MAPK activation in cells. In accordance with these observations thymidine incorporation into EGFR-expressing KB cells was selectively and potently inhibited by BIBX1382 and BIBU1361 with half-maximally effective doses in the nanomolar range. Oral administration of these compounds inhibited the growth of established human xenografts in athymic mice, including vulval and head and neck squamous cell carcinomas. Tumor growth inhibition by BIBX1382 coincided with reduced pEGFR and Ki-67 levels in vivo, which is in accordance with the expected effect of EGFR inhibitors. Collectively, these results show that the structural class of pyrimidopyrimidines, exemplified here by BIBX1382 and BIBU1361, represents an interesting scaffold for the design of EGFR inhibitors.
authors.affiliation: Department of NCE Pharmacology, Boehringer-Ingelheim Austria, Dr. Boehringer-Gasse 5-11, A-1120 Vienna, Austria. flavio.solca@vie.boehringer-ingelheim.com
authors.forename: Flavio F
authors.initials: FF
authors.lastname: Solca
authors.forename: Anke
authors.initials: A
authors.lastname: Baum
authors.forename: Elke
authors.initials: E
authors.lastname: Langkopf
authors.forename: Georg
authors.initials: G
authors.lastname: Dahmann
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Heider
authors.forename: Frank
authors.initials: F
authors.lastname: Himmelsbach
authors.forename: Jacques C A
authors.initials: JC
authors.lastname: van Meel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D007624:KB Cells; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009930:Organic Chemicals / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014844:Vulva / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C495482:(3-chloro-4-fluoro-phenyl)-(6-(4-diethylaminomethyl-piperidin-1yl)-pyrimido(5,4-d)pyrimidin-4-yl)amine; D000970:Antineoplastic Agents; C423062:BIBX 1382BS; D009930:Organic Chemicals; D010880:Piperidines; D011743:Pyrimidines; D066246:ErbB Receptors