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
J. Med. Chem., 2015, 58, 6, 2855-2861
https://doi.org/10.1021/jm501892g

Abstract

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.