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E7766, a Macrocycle‐Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan‐Genotypic Activity
Author(s) -
Kim DaeShik,
Endo Atsushi,
Fang Francis G.,
Huang KuanChun,
Bao Xingfeng,
Choi Hyeongwook,
Majumder Utpal,
Shen Young Y.,
Mathieu Steven,
Zhu Xiaojie,
Sanders Kristen,
Noland Thomas,
Hao MingHong,
Chen Yu,
Wang John Y.,
Yasui So,
TenDyke Karen,
Wu Jiayi,
Ingersoll Christy,
Loiacono Kara A.,
Hutz Janna E.,
Sarwar Nadeem
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100068
Subject(s) - stimulator of interferon genes , sting , agonist , stereoselectivity , interferon , gene , stereochemistry , chemistry , genotype , potency , nucleic acid , innate immune system , biology , biochemistry , genetics , receptor , in vitro , catalysis , engineering , aerospace engineering
A strategy for creating potent and pan‐genotypic stimulator of interferon genes (STING) agonists is described. Locking a bioactive U‐shaped conformation of cyclic dinucleotides by introducing a transannular macrocyclic bridge between the nucleic acid bases leads to a topologically novel macrocycle‐bridged STING agonist (MBSA). In addition to substantially enhanced potency, the newly designed MBSAs, exemplified by clinical candidate E7766 , exhibit broad pan‐genotypic activity in all major human STING variants. E7766 is shown to have potent antitumor activity with long lasting immune memory response in a mouse liver metastatic tumor model. Two complementary stereoselective synthetic routes to E7766 are also described.