Mechanism of human telomerase inhibition by BIBR1532, a synthetic, non-nucleosidic drug candidate.

The Journal of biological chemistry (2002-02-21)
Emanuelle Pascolo, Christian Wenz, Joachim Lingner, Norbert Hauel, Henning Priepke, Iris Kauffmann, Pilar Garin-Chesa, Wolfgang J Rettig, Klaus Damm, Andreas Schnapp

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.

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DTT, crystalline powder, =97% (Ellman′s reagent), Mr 154.3