THE JOHNS HOPKINS UNIVERSITY;LIEBER INSTITUTE FOR BRAIN DEVELOPMENT
发明人:
LAIHO, MARIKKI,COLIS, LAUREEN,BARROW, JAMES C.,ERNST, GLEN,SANDERS, SARAH
申请号：
CA2943022
公开号：
CA2943022A1
申请日:
2015.03.20
申请国别(地区):
CA
年份:
2015
代理人:
摘要：
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.
