Article
作者: Surti, Neha ; Kim, Kyoung ; Shen, Henry ; Carter, Percy H. ; Lei, Ming ; Terrett, Nicholas K. ; Naglich, Joseph G. ; Posy, Shana L. ; Pokross, Matthew E. ; Emanuel, Stuart L. ; Connors, William H. ; Borzilleri, Robert M. ; Fraley, Andrew ; Zhang, Yong ; Talbott, Randy ; Seigal, Benjamin A. ; Fargnoli, Joseph
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.