title: Synthesis and biological testing of novel pyridoisothiazolones as histone acetyltransferase inhibitors.
abstract: We present a combination of database screening, synthesis and in vitro testing to identify novel histone acetyltransferase (HAT) inhibitors. The National Cancer Institute compound collection (NCI) and several commercial databases were filtered by similarity-based virtual screening to find new HAT inhibitors. Employing the recombinant HAT p300/CBP-associated factor (PCAF) and two different histone substrates for screening, pyridoisothiazolones were identified as inhibitors of human PCAF. Due to the limited solubility of the initial hits, we synthesized and tested them on PCAF. The compounds inhibit the proliferation of cancer cells. In summary, valuable chemical tools and potential lead candidates for new anticancer agents directed against HATs as new targets have been identified.
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs-University of Freiburg, Germany.
authors.forename: Silviya D
authors.initials: SD
authors.lastname: Furdas
authors.forename: Suhaib
authors.initials: S
authors.lastname: Shekfeh
authors.forename: Elisabeth-Maria
authors.initials: EM
authors.lastname: Bissinger
authors.forename: Julia M
authors.initials: JM
authors.lastname: Wagner
authors.forename: Sonja
authors.initials: S
authors.lastname: Schlimme
authors.forename: Vassil
authors.initials: V
authors.lastname: Valkov
authors.forename: Michael
authors.initials: M
authors.lastname: Hendzel
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry*; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011725:Pyridines; D013844:Thiazoles; C001490:3-isothiazolone; D051548:Histone Acetyltransferases