POL I program
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RNA Polymerase I Program: Non-Genotoxic Activators of p53
Targeted Inhibition of RNA Polymerase I
The tumor suppressor protein p53, known as “the guardian of the genome”, determines cellular responses to diverse stress factors and is pivotal in killing cancer cells. Activation of p53 by agents that do not damage cellular DNA has long been an attractive approach to treating cancers, yet it has not been successfully exploited in the clinical setting. Activation of p53 is especially relevant for the treatment of hematologic malignancies, in which the vast majority of cancers have wild-type p53 status.
Control of p53 activation is regulated through Nucleolar Stress Signaling Pathway or the Oncogenic/Genotoxic Stress Pathways. Many chemotherapeutic agents effectively activate p53 through genotoxic insult, but such agents also damage DNA in normal cells, resulting in significant toxicities. Activation of p53 through the Nucleolar Stress Signaling Pathway can be accomplished by small molecule inhibition of the RNA Polymerase I (Pol I) enzyme in the nucleolus without damaging DNA, thereby representing the ideal, non-genotoxic path to activate p53 and selectively kill cancer cells.
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. cGMP manufacture has been completed and the molecule is being advanced to the clinic and will be developed for the treatment of leukemias, lymphomas and multiple myeloma.
