posted on 2015-07-09, 00:00authored byYong 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.