CX-5461, a selective inhibitor of rRNA synthesis, suppresses Pol I-driven transcription of rRNA.

CX-5461 dihydrochloride is a potent, orally active inhibitor of Pol I-mediated rRNA synthesis that acts on HCT-116 cells (IC50: 142 nM), A375 cells (IC50: 113 nM) and MIA PaCa-2 cells (IC50: 54 nM), and to a lesser extent on Pol II (IC50 ≥ 25 μM).

Pidnarulex HCl is the salt form of CX-5461, a first-in-class non-genotoxic small molecule targeted inhibitor of RNA polymerase I (Pol I) that activates the p53 pathway without causing DNA damage. CX-5461 selectively inhibits rRNA synthesis by Pol I in the nucleolus, but does not inhibit mRNA synthesis by RNA Polymerase II (Pol II) and does not inhibit DNA replication or protein synthesis. Inhibition of Pol I results in nucleolar stress and release of ribosomal proteins (RP) from the nucleolus. The RP bind to Mdm2 and liberate p53 to orchestrate apoptosis in cancer cells. CX-5461 demonstrates a favorable preclinical profile, potently and selectively kills cancer cells, demonstrates robust in vivo efficacy in multiple models, and has demonstrated oral bioavailability in multiple species.

EML-405 is a small-molecule inhibitor of SPIN1 ( Kd of 14 uM).