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

Benjamin A. Seigal | Zendy; William H. Connors | Zendy; Andrew W. Fraley | Zendy; R. M. Borzilleri | Zendy; Percy H. Carter | Zendy; Stuart L. Emanuel | Zendy; Joseph Fargnoli | Zendy; Kyoung Kim | Zendy; Ming Lei | Zendy; Joseph G. Naglich | Zendy; Matthew Pokross | Zendy; Shana L. Posy | Zendy; Henry Shen | Zendy; Neha Surti | Zendy; Randy Talbott | Zendy; Yong Zhang | Zendy; N.K. Terrett | Zendy

Open Access

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

Author(s) -

Benjamin A. Seigal,

William H. Connors,

Andrew W. Fraley,

R. M. Borzilleri,

Percy H. Carter,

Stuart L. Emanuel,

Joseph Fargnoli,

Kyoung Kim,

Ming Lei,

Joseph G. Naglich,

Matthew Pokross,

Shana L. Posy,

Henry Shen,

Neha Surti,

Randy Talbott,

Yong Zhang,

N.K. Terrett

Publication year - 2015

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/jm501892g

Subject(s) - xiap , chemistry , in vivo , apoptosis , cocrystal , lead compound , inhibitor of apoptosis , dna , combinatorial chemistry , caspase , in vitro , stereochemistry , cancer research , programmed cell death , biochemistry , molecule , genetics , hydrogen bond , organic chemistry , biology

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.

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