CX-5461 is a potent, orally bioavailable small molecule inhibitor of rRNA synthesis in cancer cells. It selectively inhibits rRNA synthesis by polymerase I (Pol I) in the nucleolus, but does not inhibit mRNA synthesis by RNA Polymerase II (Pol II), DNA replication or protein synthesis. (In tested cell lines, IC50s for Pol I range from 54nmol/L to 142nmol/L, IC50s for Pol II is higher than 25umol/L.)

CX-5461 exhibits a broad range of antiproliferative activity, with wild-type (wt) p53 cells derived from hematological malignancies being the most sensitive. (p53 wt solid tumors: median IC50=164 nM; p53 wt hematologic cancers cells: median IC50=25 nM). CX-5461 selectively kills cancer cells relative to normal cells. (Median IC50 in normal cells is 5,000 nM.) CX-5461 directly targets the initiation stage of rRNA synthesis, induces both autophagy and senescene, but not apoptosis in a p53-independent process in solid tumor cell lines. In wt p53 hematologic cancer cells, however, inhibition of Pol I results in nucleolar stress and release of ribosomal proteins (RP) from the nucleolus. The RP bind to Mdm2 and release p53 to cause apoptosis in cancer cells. CX-5461 exhibits potent in vivo antitumor activity against both human solid tumor in xenograft models, and leukemia and lymphoma in animal models [1-2].