Getting A Clue About Cortistatin's Activity

The natural product cortistatin A is a sought-after target for synthetic chemists because it selectively blocks cellular activities known to be necessary for blood vessel growth. That bioactivity could lead to new therapies for cancers and vision impairments where vessel growth is out of whack. However, the biological targets for cortistatin A and its cortistatin “siblings” have remained elusive. Guided by the knowledge that cortistatin’s isoquinoline ring—which is critical for its activity—is a hallmark of kinase inhibitors, Victor J. Cee and Matthew R. Lee of Amgen; David Y.-K. Chen of Singapore’s Agency for Science, Technology & Research; and K. C. Nicolaou of Scripps Research Institute examined cortistatin A’s affinity for a large panel of kinases (Angew. Chem. Int. Ed., DOI: 10.1002/anie.200904778). They learned that cortistatin A binds tightly to a trio of kinases with a variety of biological roles. Molecular modeling experiments suggest that the isoquinoline ring makes key interactions with the kinases’ ATP binding pockets. However, the team cautions that further work is necessary to link the kinase-binding activity to cortistatin’s potent bioactivity.