Dimeric Macrocyclic Antagonists of Inhibitor of Apoptosis Proteins for the Treatment of Cancer

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 me...

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Published in:ACS medicinal chemistry letters 2015-07, Vol.6 (7), p.770-775
Main Authors: Zhang, Yong, Seigal, Benjamin A, Terrett, Nicholas K, Talbott, Randy L, Fargnoli, Joseph, Naglich, Joseph G, Chaudhry, Charu, Posy, Shana L, Vuppugalla, Ragini, Cornelius, Georgia, Lei, Ming, Wang, Chunlei, Zhang, Yingru, Schmidt, Robert J, Wei, Donna D, Miller, Michael M, Allen, Martin P, Li, Ling, Carter, Percy H, Vite, Gregory D, Borzilleri, Robert M
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Language:English
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Letter
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Summary: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.5b00091