LIEBER INSTITUTE FOR BRAIN DEVELOPMENT;THE JOHNS HOPKINS UNIVERSITY
发明人:
Marikki Laiho,Laureen Colis,James C. Barrow,Glen Ernst,Sarah Sanders
申请号：
US15126588
公开号：
US20170081322A1
申请日:
2015.03.20
申请国别(地区):
US
年份:
2017
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.
