MedKoo product information:

 CX-5461

Description of CX-5461: CX-5461 is 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. (source: Cylene Pharmaceuticals website)

Current developer:    Cylene Pharmaceuticals.

Highlight of recent research on CX-5461

Data published in 2010 by Cylene Pharmaceuticals

Anticancer activity of CX-5461: CX-5461 selectively inhibits Pol I–driven transcription relative to Pol II–driven transcription, DNA replication, and protein translation. Molecular studies demonstrate that CX-5461 inhibits the initiation stage of rRNA synthesis and induces both senescence and autophagy, but not apoptosis, through a p53-independent process in solid tumor cell lines. CX-5461 is orally bioavailable and demonstrates in vivo antitumor activity against human solid tumors in murine xenograft models. Our findings position CX-5461 for investigational clinical trials as a potent, selective, and orally administered agent for cancer treatment. Cancer Res; 71(4); 1418–30.

1: Drygin D, Lin A, Bliesath J, Ho CB, O'Brien SE, Proffitt C, Omori M, Haddach M, Schwaebe MK, Siddiqui-Jain A, Streiner N, Quin JE, Sanij E, Bywater MJ, Hannan RD, Ryckman D, Anderes K, Rice WG. Targeting RNA polymerase I with an oral small  molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. Cancer Res. 2011 Feb 15;71(4):1418-30. Epub 2010 Dec 15. PubMed PMID: 21159662.

Chemical synthesis of CX-4561:

1. Schwaebe, Michael K.; Ryckman, David M.; Nagasawa, Johnny Y.; Pierre, Fabrice; Vialettes, Anne; Haddach, Mustapha.  Facile and efficient generation of quinolone amides from esters using aluminum chloride. Tetrahedron Letters (2011), 52(10), 1096-1100.

2. Nagasawa, Johnny Yasuo; Pierre, Fabrice; Haddach, Mustapha; Schwaebe, Michael; Darjania, Levan; Whitten, Jeffrey P.  Quinolone analogs useful in the inhibition of cell proliferation and/or induce cell apoptosis and their preparation. PCT Int. Appl. (2009), WO 2009046383.