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The conversion of the cellular prion protein (PrPc) into pathologic PrPSc and the accumulation of aggregated PrPSc are hallmarks of prion diseases. A variety of experimental approaches to interfere with prion conversion have been reported. The aim of this work was to investigate whether interference with intracellular signalling events has an impact on this conversion process. Therefore, about 50 inhibitors of specific signalling pathways were screened in prion-infected cells for their capacity to affect prion conversion. The tyrosine kinase inhibitor STI571 was highly effective against PrPSc propagation, with an IC50 of less than 1 µM. STI571 cleared prion-infected cells time- and dose-dependently from PrPSc without influencing biogenesis, localization or biochemical features of PrPc. Interestingly, this compound did not interfere with the de novo formation of PrPSc but mainly activated the lysosomal degradation of pre-existing PrPSc, lowering the half-life time of PrPSc from >24 hours to <9 hours. The data indicate that among those kinases known to be inhibited by STI571, c-Abl is the most probable target responsible for the observed anti-prion effect. Taken together, treatment with STI571 profoundly activates the lysosomal degradation of PrPSc. Therefore, substances specifically interfering with cellular signalling pathways might represent a novel class of anti-prion compounds.