CX-5461 | RNA Polymerase I inhibitor

CX-5461 (1138549-36-6) is a first-in-class selective RNA polymerase I inhibitor, suppressing Pol I transcription in MV 4;11 myelomonocytic leukemia cells and SR immunoblastic lymphoma cells with EC₅₀ values of 95 and 135 nM respectively and demonstrating 200-fold selectivity over Pol II.^1,2  Activates the DNA damage response.³ It induces a rapid accumulation of cytosolic DNA which results in upregulation of STING.⁴ Acts as a potent immunosuppressant inhibiting T cell-mediated alloimmunity and representing a novel class of immunosuppressant.⁵

References/Citations:

1. Drygin et al. (2011), Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth; Cancer Res., 71 1418
2. Haddach et al. (2012), Discovery of CX-5461, the first direct and selective inhibitor of RNA polymerase I, for cancer therapeutics; ACS Med. Chem. Lett., 3 602
3. Sanij et al. (2020), CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer; Nat. Commun., 11 2641
4. Cornelison et al. (2021), CX-5461 Treatment Leads to Cytosolic DNA-Mediated STING Activation in Ovarian Cancer; Cancers (Basel), 13 5056
5. Pan et al. (2022), CX-5461 is a potent immunosuppressant which inhibits T cell-mediated alloimmunity via p53-DUSP5; Pharmacol. Res., 177 106120