Mechanism of human telomerase inhibition by BIBR1532, a synthetic, non-nucleosidic drug candidate.
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.
Pascolo
Emanuelle
E
Boehringer Ingelheim Pharma KG, Department of Oncology Research, Birkendorfer Strasse 65, 88397 Biberach, Germany.
Wenz
Christian
C
Lingner
Joachim
J
Hauel
Norbert
N
Priepke
Henning
H
Kauffmann
Iris
I
Garin-Chesa
Pilar
P
Rettig
Wolfgang J
WJ
Damm
Klaus
K
Schnapp
Andreas
A
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*
D062365:Aminobenzoates; C458523:BIBR 1532; D017931:DNA Primers; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D011994:Recombinant Proteins; D012194:RNA-Directed DNA Polymerase; D019098:Telomerase