Abstract: RNA polymerase I (Pol I) is a dedicated polymerase for the transcription of the 47S ribosomal RNA precursor subsequently processed into the mature 5.8S, 18S and 28S ribosomal RNAs and assembled into ribosomes in the nucleolus. Pol I activity is commonly deregulated in human cancers. Based on the discovery of lead molecule BMH-21, a series of pyridoquinazolinecarboxamides were synthesized as inhibitors of Pol I and activators of the destruction of RPA194, the Pol I large catalytic subunit protein. The present invention identifies a set of bioactive compounds, including purified stereoisomers, that potently cause RPA194 degradation that function in a tightly constrained chemical space. Pharmaceutical compositions comprising these compounds and their uses in cancer and other Pol I related diseases is also provided.

Abstract: RNA polymerase I (Pol I) is a dedicated polymerase for the transcription of the 47S ribosomal RNA precursor subsequently processed into the mature 5.8S, 18S and 28S ribosomal RNAs and assembled into ribosomes in the nucleolus. Pol I activity is commonly deregulated in human cancers. Based on the discovery of lead molecule BMH-21, a series of pyridoquinazolinecarboxamides were synthesized as inhibitors of Pol I and activators of the destruction of RPA194, the Pol I large catalytic subunit protein. The present invention identifies a set of bioactive compounds, including purified stereoisomers, that potently cause RPA194 degradation that function in a tightly constrained chemical space. Pharmaceutical compositions comprising these compounds and their uses in cancer and other Pol I related diseases is also provided.

Abstract: The invention presents methods of identifying small molecule compounds that are activators of tumor suppressor protein p53 pathway, and its associated family members p63 and p73, function. The invention is further drawn to methods of killing tumor cells and treating cancers or other conditions requiring activation of the p53 family member pathways and DNA damage response pathways with the small molecules.

Abstract: RNA polymerase I (Pol I) is a dedicated polymerase for the transcription of the 47S ribosomal RNA precursor subsequently processed into the mature 5.8S, 18S and 28S ribosomal RNAs and assembled into ribosomes in the nucleolus. Pol I activity is commonly deregulated in human cancers. Based on the discovery of lead molecule BMH-21, a series of pyridoquinazolinecarboxamides were synthesized as inhibitors of Pol I and activators of the destruction of RPA194, the Pol I large catalytic subunit protein. The present invention identifies a set of bioactive compounds, including purified stereoisomers, that potently cause RPA194 degradation that function in a tightly constrained chemical space. Pharmaceutical compositions comprising these compounds and their uses in cancer and other Pol I related diseases is also provided.

Abstract: The invention presents methods of identifying small molecule compounds that are activators of tumor suppressor protein p53 pathway, and its associated family members p63 and p73, function. The invention is further drawn to methods of killing tumor cells and treating cancers or other conditions requiring activation of the p53 family member pathways and DNA damage response pathways with the small molecules.

Abstract: The invention presents methods of identifying small molecule compounds that are activators of tumor suppressor protein p53 pathway, and its associated family members p63 and p73, function. The invention is further drawn to methods of killing tumor cells and treating cancers or other conditions requiring activation of the p53 family member pathways and DNA damage response pathways with the small molecules.

Abstract: The invention presents methods of identifying small molecule compounds that are activators of tumor suppressor protein p53 pathway, and its associated family members p63 and p73, function. The invention is further drawn to methods of killing tumor cells and treating cancers or other conditions requiring activation of the p53 family member pathways and DNA damage response pathways with the small molecules.