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