title: Novel chimeric histone deacetylase inhibitors: a series of lapatinib hybrides as potent inhibitors of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and histone deacetylase activity.
abstract: Reversible lysine-specific acetylation has been described as an important posttranslational modification, regulating chromatin structure and transcriptional activity in the case of core histone proteins. Histone deacetylases (HDAC) are considered as a promising target for anticancer drug development, with 2a as pan-HDAC inhibitor approved for cutanous T-cell lymphoma therapy and several other HDAC inhibitors currently in preclinical and clinical development. Protein kinases are a well-established target for cancer therapy with the EGFR/HER2 inhibitor 5 approved for treatment of advanced, HER2 positive breast cancer as a prominent example. In the present report, we present a novel strategy for cancer drug development by combination of EGFR/HER2 kinase and HDAC inhibitory activity in one molecule. By combining the structural features of 5 with an (E)-3-(aryl)-N-hydroxyacrylamide motif known from HDAC inhibitors like 1 or 3, we obtained selective inhibitors for both targets with potent cellular activity (target inhibition and cytotoxicity) of selected compounds 6a and 6c. By combining two distinct pharmacologically properties in one molecule, we postulate a broader activity spectrum and less likelihood of drug resistance in cancer patients.
authors.affiliation: Department of Pharmaceutical Chemistry I, University of Regensburg, D-93040 Regensburg, Germany. siavosh.mahboobi@chemie.uni-regensburg.de
authors.forename: Siavosh
authors.initials: S
authors.lastname: Mahboobi
authors.forename: Andreas
authors.initials: A
authors.lastname: Sellmer
authors.forename: Matthias
authors.initials: M
authors.lastname: Winkler
authors.forename: Emerich
authors.initials: E
authors.lastname: Eichhorn
authors.forename: Herwig
authors.initials: H
authors.lastname: Pongratz
authors.forename: Thomas
authors.initials: T
authors.lastname: Ciossek
authors.forename: Thomas
authors.initials: T
authors.lastname: Baer
authors.forename: Thomas
authors.initials: T
authors.lastname: Maier
authors.forename: Thomas
authors.initials: T
authors.lastname: Beckers
mesh_terms: D000107:Acetylation; D000178:Acrylamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D000077341:Lapatinib; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D007527:Isoenzymes; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human