1. Dimeric Macrocyclic Antagonists of Inhibitor of Apoptosis Proteins for the Treatment of Cancer
- Author
-
Georgia Cornelius, Joseph Fargnoli, Joseph G. Naglich, Yong Zhang, Shana L. Posy, Benjamin A. Seigal, Charu Chaudhry, Ling Li, Yingru Zhang, Ragini Vuppugalla, Robert J. Schmidt, Percy H. Carter, Gregory D. Vite, Ming Lei, Martin Patrick Allen, Donna D. Wei, Chunlei Wang, Michael M. Miller, Randy Talbott, Robert M. Borzilleri, and Nicholas K. Terrett
- Subjects
Antitumor activity ,Inhibitor of apoptosis domain ,Chemistry ,Organic Chemistry ,Cancer ,Inhibitor of apoptosis ,medicine.disease ,Biochemistry ,Molecular biology ,XIAP ,Apoptosis ,Cell culture ,Drug Discovery ,medicine ,Cancer research ,Human melanoma - Abstract
A series of dimeric macrocyclic compounds were prepared and evaluated as antagonists for inhibitor of apoptosis proteins. The most potent analogue 11, which binds to XIAP and c-IAP proteins with high affinity and induces caspase-3 activation and ultimately cell apoptosis, inhibits growth of human melanoma and colorectal cell lines at low nanomolar concentrations. Furthermore, compound 11 demonstrated significant antitumor activity in the A875 human melanoma xenograft model at doses as low as 2 mg/kg on a q3d schedule.
- Published
- 2015