The product of the DKC1 gene, dyskerin, is required for both ribosome biogenesis and telomerase complex stabilization. Targeting these cellular processes has been explored for the development of drugs to selectively or preferentially kill cancer cells. Presently, intense research is conducted involving the identification of new biological targets whose modulation may simultaneously interfere with multiple cellular functions that are known to be hyper-activated by neoplastic transformations.Here, we report the identification of small molecules able to inhibit dyskerin catalytic activity. Different in silico techniques were applied to select compounds and analyze the binding modes and the interaction patterns of ligands in the human dyskerin catalytic site. We also describe a newly developed and optimized fast real-time PCR assay that was used to detect dyskerin pseudouridylation activity in vitro.The identification of new dyskerin inhibitors constitute the first proof of principle that the pseudouridylation activity can be modulated through the usage of small molecule agents. The presented results indicate an alternative therapeutic strategy to target ribosome biogenesis pathway.

Inhibition of human dyskerin as a new approach to target ribosome biogenesis

248th National Meeting (2014)

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