Figure 1. Pol I inhibition in cancer. Researchers from the Peter MacCallum Research Centre and Cylene Pharmaceuticals Inc. have published data in Cancer Cell showing that a small molecule inhibitor of RNA polymerase I (Pol I) reduced growth of hematological cancers in mice.

In lymphoma cells, the Pol I inhibitor CX-5461 blocked Pol I with low nanomolar potency [a], triggering a stress response involving the release of ribosomal proteins from the nucleolus [b], a subcompartment of the nucleus. The ribosomal proteins then blocked interactions between p53 and the p53 inhibitory protein mdm2 p53 binding protein homolog (MDM2; HDM2) [c], which in turn activated p53 [d] and allowed it to upregulate expression of proapoptotic genes, killing the cancer cells [e].

Cylene and Peter MacCallum plan to start a Phase I trial of CX-5461 to treat hematological malignancies this year.