American Chemical Society
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Dimeric Macrocyclic Antagonists of Inhibitor of Apoptosis Proteins for the Treatment of Cancer

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journal contribution
posted on 2015-07-09, 00:00 authored by Yong Zhang, Benjamin A. Seigal, Nicholas K. Terrett, Randy L. Talbott, Joseph Fargnoli, Joseph G. Naglich, Charu Chaudhry, Shana L. Posy, Ragini Vuppugalla, Georgia Cornelius, Ming Lei, Chunlei Wang, Yingru Zhang, Robert J. Schmidt, Donna D. Wei, Michael M. Miller, Martin P. Allen, Ling Li, Percy H. Carter, Gregory D. Vite, Robert M. Borzilleri
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.