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The Discovery of Macrocyclic XIAP Antagonists from a DNA-Programmed Chemistry Library, and Their Optimization To Give Lead Compounds with in Vivo Antitumor Activity

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journal contribution
posted on 2015-12-17, 07:45 authored by Benjamin A. Seigal, William H. Connors, Andrew Fraley, Robert M. Borzilleri, Percy H. Carter, Stuart L. Emanuel, Joseph Fargnoli, Kyoung Kim, Ming Lei, Joseph G. Naglich, Matthew E. Pokross, Shana L. Posy, Henry Shen, Neha Surti, Randy Talbott, Yong Zhang, Nicholas K. Terrett
Affinity selection screening of macrocycle libraries derived from DNA-programmed chemistry identified XIAP BIR2 and BIR3 domain inhibitors that displace bound pro-apoptotic caspases. X-ray cocrystal structures of key compounds with XIAP BIR2 suggested potency-enhancing structural modifications. Optimization of dimeric macrocycles with similar affinity for both domains were potent pro-apoptotic agents in cancer cell lines and efficacious in shrinking tumors in a mouse xenograft model.