title: Mechanism of human telomerase inhibition by BIBR1532, a synthetic, non-nucleosidic drug candidate.
abstract: Telomerase, a ribonucleoprotein acting as a reverse transcriptase, has been identified as a target for cancer drug discovery. The synthetic, non-nucleosidic compound, BIBR1532, is a potent and selective telomerase inhibitor capable of inducing senescence in human cancer cells (). In the present study, the mode of drug action was characterized. BIBR1532 inhibits the native and recombinant human telomerase, comprising the human telomerase reverse transcriptase and human telomerase RNA components, with similar potency primarily by interfering with the processivity of the enzyme. Enzyme-kinetic experiments show that BIBR1532 is a mixed-type non-competitive inhibitor and suggest a drug binding site distinct from the sites for deoxyribonucleotides and the DNA primer, respectively. Thus, BIBR1532 defines a novel class of telomerase inhibitor with mechanistic similarities to non-nucleosidic inhibitors of HIV1 reverse transcriptase.
authors.affiliation: Boehringer Ingelheim Pharma KG, Department of Oncology Research, Birkendorfer Strasse 65, 88397 Biberach, Germany.
authors.forename: Emanuelle
authors.initials: E
authors.lastname: Pascolo
authors.forename: Christian
authors.initials: C
authors.lastname: Wenz
authors.forename: Joachim
authors.initials: J
authors.lastname: Lingner
authors.forename: Norbert
authors.initials: N
authors.lastname: Hauel
authors.forename: Henning
authors.initials: H
authors.lastname: Priepke
authors.forename: Iris
authors.initials: I
authors.lastname: Kauffmann
authors.forename: Pilar
authors.initials: P
authors.lastname: Garin-Chesa
authors.forename: Wolfgang J
authors.initials: WJ
authors.lastname: Rettig
authors.forename: Klaus
authors.initials: K
authors.lastname: Damm
authors.forename: Andreas
authors.initials: A
authors.lastname: Schnapp
mesh_terms: D062365:Aminobenzoates; D001665:Binding Sites; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D009281:Naphthalenes; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D019098:Telomerase / Q000037:antagonists & inhibitors*
chemical_list: D062365:Aminobenzoates; C458523:BIBR 1532; D017931:DNA Primers; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D011994:Recombinant Proteins; D012194:RNA-Directed DNA Polymerase; D019098:Telomerase